Selective Androgen Receptor Modulators

ABSTRACT

This invention provides compounds of formula I, pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable excipient, methods of modulating the androgen receptor, methods of treating diseases beneficially treated by an androgen receptor modulator (e.g., sarcopenia, prostate cancer, contraception, type 2 diabetes related disorders or diseases, anemia, depression, and renal disease) and processes for making compounds and intermediates useful in the preparation of same.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/387,440, filed on Sep. 28, 2010. The entire teachings of the aboveapplication are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Androgen signaling is mediated through the androgen receptor (AR) and isa nuclear signaling pathway of tremendous importance in mammals. Inaddition to its primary role in sexual development, maturation andmaintenance of sexual function in both males and females, this criticalhormone signaling pathway affects a large number of non-sexual tissuesincluding, bone, muscle, CNS, liver, etc. In humans, testosterone anddihydrotestosterone are the primary ligands that mediate AR-signaling.Both are high affinity ligands for AR, with dihydrotestosterone havingsomewhat higher affinity. Testosterone is converted todihydrotestosterone through the action of 5α-reductase enzymes and isconverted to 17β-estradiol (potent endogenous estrogen) through theaction of P-450 aromatase enzymes. AR signaling is mediated by bindingof an AR ligand to AR in the cellular cytosol, homodimerization of twoAR receptors and nuclear location of the ligand bound dimer to the cellnucleus where the complex associates with various coactivators as wellas Androgen Response Elements (palindrome-like sequences of DNA) whichserve as activation sites for certain AR-mediated genes. Due to the verylarge number of AR target tissues, both sexual and non-sexual, androgenssuch as testosterone and dihydrotestosterone have a number ofpotentially desirable actions as well as non-desirable actions dependingon the particular individual's age, sex, therapeutic need, etc. In theadult male and female, certain positive consequences of AR-agonistsignaling can be generalized as including increased bone mineral densityand a corresponding reduction of risk of bone fractures. Accordingly,androgen supplementation can be very valuable in the prevention ortreatment of osteoporosis where the osteoporosis might originate fromany number of different causes, such as corticosteroid inducedosteoporosis and age-related osteoporosis (e.g. post-menopausal).Likewise, males and females respond to agonist supplementation with anincrease in muscle mass and very often a decrease in fat mass. This isbeneficial in a very large number of treatment modalities. For example,there are many wasting syndromes associated with different diseasestates where the therapeutic goal is for a patient to maintain weightand function, such as the treatment of cancer associated cachexia,AIDs-related cachexia, anorexia and many more. Other muscle-wastingdisorders such as muscular dystrophy in its many forms as well asrelated disorders might be treated to advantage with androgens. Theincrease in muscle mass with concomitant reduction in fat massassociated with anabolic androgen action has additional health benefitsfor many men and women including potentially increased sensitivity toinsulin. Androgen supplementation is also associated with reduction ofhigh triglycerides, though there is a general correlation with androgenuse and decreased HDL levels and in some cases, increased LDL levels. Inthe CNS, numerous laudatory benefits have been associated with androgensupplementation including improved sexual desire and functioning,increased cognition, memory, sense of well being and possible decreasein risk of Alzheimer's disease.

Androgen antagonists have been used in treating prostate cancer, whereblockade of androgen signaling is desired whereas some androgensagonists (e.g. dihydrotestosterone) stimulate the hypertrophy ofprostate tissue and may be a causative factor in prostate cancer.Androgen agonist activity is often associated with stimulation of benignprostate hyperplasia, a disease characterized by an enlarged prostateoften accompanied by discomfort and difficulty in urination due toblockage of the urethra. As a result, androgen antagonists have efficacyin the reduction of the size of the prostate and the correspondingsymptoms of benign prostate hyperplasia, though it is much more commonto use a 5α-reductase inhibitor (e.g. finasteride) as such inhibitors donot decrease androgen signaling systemically to the same extent as atypical anti-androgen (e.g. bicalutamide), but rather reduce androgendrive more site specifically to where testosterone to DHT conversionoccurs such as the prostate and scalp. Androgen antagonists also findutility in the treatment of hirsutism in women as well as the treatmentof acne. Androgens are generally contraindicated in conditions that aretreated with androgen antagonists since they can exacerbate the symptomsthat are being treated.

Ideally, an androgen would retain the benefits of androgen agonistswhile minimizing the stimulatory effects on the prostate in males aswell as some of the other untoward effects of androgens includingmasculinization of women and increase in acne in both sexes. Androgensthat demonstrate tissue selective effects compared to the benchmarkstestosterone and/or dihydrotestosterone are typically referred to asandrogen receptor modulators or more often, selective androgen receptormodulators (SARMs). At the far end of potential selectivity, an idealSARM would demonstrate no prostate stimulation while maintaining orgrowing muscle sufficient to effectively mimic the effects oftestosterone or dihydrotestosterone. The growing appreciation of thepositive contribution that SARMs can make in the many therapeutic areaswhere androgen activity is desirable has led to a large amount ofresearch into this important area. Due to a compelling need for noveland effective androgen therapies with potentially reduced side effects,novel and effective SARM compounds are urgently needed.

SUMMARY OF THE INVENTION

In certain embodiments, this invention describes a compound of formula I

wherein R_(x) is CN, Cl, Br, NO₂ or R_(x1);R_(y) is CH₃, CF₃, or halogen;R_(z) is hydrogen or optionally C₁₋₃alkyl, C₂₋₃alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃ haloalkyl, NO₂, NH₂, OMe, halogen or OH; orR_(y) and R_(z) together form

wherein R_(y′) is optionally a substituent selected from the groupconsisting of halogen, C₁₋₃alkyl, C₁₋₃haloalkyl and OH;R_(x1) is a 5 member heteroaryl, said heteroaryl selected from

R′ is hydrogen or optionally C₁-C₂ alkyl, CF₃, or halogen; orR_(x) and R_(y) together with the phenyl group to which they areattached form a 5 member aromatic ring selected from:

wherein each R″ is independently hydrogen or optionally CF₃, or C₁-C₂alkyl;P₁ is hydrogen or a metabolically labile group;R_(a) and R_(b) are each independently selected from hydrogen or C₁-C₃alkyl; andX is CH₂, O or NR_(c); whereinR_(c) is hydrogen or C₁-C₃ alkyl;or pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

In certain embodiments, this invention describes a compound of formula I

wherein R_(x) is CN, Cl, Br, NO₂ or R_(x1);R_(y) is CH₃, CF₃, or halogen;R_(z) is hydrogen or optionally C₁₋₃alkyl, C₂₋₃alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃ haloalkyl, NO₂, NH₂, OMe, halogen or OH; orR_(y) and R_(z) together form

wherein R_(y′) is optionally a substituent selected from the groupconsisting of halogen, C₁₋₃alkyl, C₁₋₃haloalkyl and OH;R_(x1) is a 5 member heteroaryl, said heteroaryl selected from

R′ is hydrogen or optionally C₁-C₂ alkyl, CF₃, or halogen; orR_(x) and R_(y) together with the phenyl group to which they areattached form a 5 member aromatic ring selected from:

wherein each R″ is independently hydrogen or optionally CF₃, or C₁-C₂alkyl;P₁ is hydrogen or a metabolically labile group;R_(a) and R_(b) are each independently selected from hydrogen or C₁-C₃alkyl; andX is CH₂, O or NR_(C); whereinR_(c) is hydrogen or C₁-C₃ alkyl;or pharmaceutically acceptable salts thereof.

In some embodiments of this invention, the compound of formula I is acompound of structure Ia:

In certain embodiments of this invention, the compound of formula I is acompound of formula Ib:

In certain embodiments, the animal to be administered the compound offormula I, Ia or Ib is a mammal. In some embodiments, that mammal is ahuman.

In certain embodiments of this invention, for the compound of formula I,Ia or Ib, R_(x) is CN.

In certain embodiments of this invention, for the compound of formula I,Ia or Ib, R_(y) is CF₃ or Cl.

In certain embodiments of this invention, for the compound of formula I,Ia or Ib, R_(z) is C₁₋₃ alkyl, hydrogen, halogen, C₁₋₃ hydroxyalkyl orC₂ alkenyl.

In some embodiments of this invention, for the compound of formula I, Iaor Ib, R_(z) is hydrogen.

In certain embodiments of this invention, for the compound of formula I,Ia or Ib, R_(x) is CN, R_(y) is CF₃ or C₁ and R_(z) is CH₃ or hydrogen.

In some embodiments, for the compound of formula I, Ia or Ib, X is CH₂.

In certain embodiments, for the compound of formula I, Ia or Ib, X isNCH₃.

In some embodiments, for the compound of formula I, Ia or Ib, X is O.

In certain embodiments, for the compound of formula I, Ia or Ib, R_(a)is hydrogen and R_(b) is hydrogen.

In some embodiments, for the compound of formula I, Ia or Ib, R_(a) isCH₃ and R_(b) is hydrogen.

In certain embodiments, for the compound of formula I, Ia or Ib, R_(a)is hydrogen and R_(b) is methyl.

In some embodiments, for the compound of formula I, Ia or Ib, R_(a) andR_(b) are each methyl.

In some embodiments, for the compound of formula I, Ia or Ib, P₁ ishydrogen or a metabolically labile group that after oral administrationin a mammal leaves P₁ as hydrogen. In some embodiments, the mammal is ahuman.

In certain embodiments, for the compound of formula I, Ia or Ib, P₁ isan alkyl acyl group containing up to 20 carbons, aryl acyl groupcontaining up to 18 carbons, alkyl ether containing up to 12 carbons,sulfate, or phosphate.

In certain embodiments, for the compound of formula I, Ia or Ib, P₁ ishydrogen, SO₃ ⁻, PO₃ ²⁻, C₁₋₃alkyl, C(═O)—C₁₋₁₀ alkyl and C(═O)(O)-aryl.

In some embodiments, for the compound of formula I, Ia or Ib, P₁ ishydrogen or C(═O)—C₁₋₆ alkyl.

In some embodiments, P₁ is hydrogen.

In some embodiments of this invention, a compound of formula II, IIa andIIb are described:

wherein R_(x) is CN, R_(y) is CF₃ or Cl and R_(z) is hydrogen or CH₃;

R_(a) is CH₃ and R_(b) is hydrogen; and

P₁ is hydrogen.

In some embodiments, for the compound of formula II, IIa and IIb:

R_(x) is CN, R_(y) is CF₃ or Cl and R_(z) is hydrogen or CH₃;

R_(a) is hydrogen and R_(b) is hydrogen; and

P₁ is hydrogen.

In some embodiments, this invention describes a compound of formula III,IIIa and IIIb

wherein R_(x) is CN, R_(y) is CF₃ or Cl and R_(z) is hydrogen or CH₃;

R_(a) is CH₃ and R_(b) is hydrogen; and

P₁ is hydrogen.

In some embodiments, for the compound of formula III, IIIa and IIIb:

R_(x) is CN, R_(y) is CF₃ or Cl and R_(z) is hydrogen or CH₃;

R_(a) is hydrogen and R_(b) is hydrogen; and

P₁ is hydrogen.

In some embodiments, for the compound of formula IV, IVa and IVb:

wherein R_(x) is CN, R_(y) is CF₃ or Cl and R_(z) is hydrogen or CH₃;

R_(a) is CH₃, R_(b) is hydrogen and R_(c) is CH₃; and

P₁ is hydrogen.

In some embodiments, for the compound of formula IV, IVa and IVb:

R_(x) is CN, R_(y) is CF₃ or Cl and R_(z) is hydrogen or CH₃;

R_(a) is hydrogen, R_(b) is hydrogen and R_(c) is CH₃; and

P₁ is hydrogen.

In certain embodiments, this invention includes a compound of formula Ithrough IV wherein the compound of formula I through IV is predominatelyone diastereomer. In this context, the term “predominately” means thecompound of formula I through IV is more than 50% of a singlediastereomer.

In some embodiments, the compound of formula I through IV is more than60% of a single diastereomer.

In some embodiments, the compound of formula I through IV is more than70% of a single diastereomer.

In some embodiments, the compound of formula I through IV is more than80% of a single diastereomer.

In some embodiments, the compound of formula I through IV is more than90% of a single diastereomer.

In some embodiments, the compound of formula I through IV is more than95% of a single diastereomer.

In some embodiments, the compound of formula I through IV is more than98% of a single diastereomer.

In some embodiments, the compound of formula I through IV is more than99% of a single diastereomer.

In some embodiments, the compound of formula I through IV is more than99.9% of a single diastereomer.

In certain embodiments, this invention includes a compound of formula Ithrough IV wherein the compound of formula I through IV is predominatelyone enantiomer. In this context, the term “predominately” means thecompound of formula I through IV has an ee of greater than 50%.

In some embodiments, the compound of formula I through IV has an ee ofgreater than 60%.

In some embodiments, the compound of formula I through IV has an ee ofgreater than 70%.

In some embodiments, the compound of formula I through IV has an ee ofgreater than 80%.

In some embodiments, the compound of formula I through IV has an ee ofgreater than 90%.

In some embodiments, the compound of formula I through IV has an ee ofgreater than 95%.

In some embodiments, the compound of formula I through IV has an ee ofgreater than 98%.

In some embodiments, the compound of formula I through IV has an ee ofgreater than 99%.

In some embodiments, the compound of formula I through IV has an ee ofgreater than 99.9%.

In some embodiments of this invention, the compound of formula I throughIV, is selected from the following list. (The compound names in the listwere generated with the assistance of ChemDraw® versions 8.0, 9.0 and/or11.0 (CambridgeSoft Corporation, 100 CambridgePark Drive, Cambridge,Mass. 02140 USA)). When the stereochemistry at a chiral center is notdefined in the compound name this indicates that the sample preparedcontained a mixture of isomers at this center.

-   4-((R)-2-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;-   4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;-   3-methyl-4-((S)-2-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;-   3-methyl-4-((S)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;-   (S)-1-(Benzo[d][1,2,3]thiadiazol-6-yl)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one;-   (S)-1-(Benzo[d][1,2,3]thiadiazol-6-yl)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one;-   4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;-   4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;-   2-chloro-4-((S)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;-   2-chloro-4-((S)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;-   2-chloro-3-methyl-4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxy    ethyl)oxazolidin-3-yl)benzonitrile;-   2-chloro-3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxy    ethyl)oxazolidin-3-yl)benzonitrile;-   3-methyl-4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoro    methyl)benzonitrile;-   3-Methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxy    ethyl)oxazolidin-3-yl)-2-(trifluoro methyl)benzonitrile;-   2-chloro-3-methyl-4-((4S,5R)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxy    ethyl)oxazolidin-3-yl)benzonitrile;-   2-chloro-3-methyl-4-((4S,5R)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;-   2-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;-   2-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;-   4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;-   4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;-   2-Chloro-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;-   2-chloro-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;-   3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;-   3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;-   4-((R)-3-methyl-2-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)imidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile;    and-   4-((R)-3-methyl-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)imidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile.

In some embodiments of this invention, the compound of formula I throughIV, is selected from the following list. (The compound names in the listwere generated with the assistance of ChemDraw®versions 8.0, 9.0 and/or11.0 (CambridgeSoft Corporation, 100 CambridgePark Drive, Cambridge,Mass. 02140 USA)). When the stereochemistry at a chiral center is notdefined in the compound name this indicates that the sample preparedcontained a mixture of isomers at this center.4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;

-   3-methyl-4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;-   4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;-   2-chloro-4-((S)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;-   2-chloro-3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxy    ethyl)oxazolidin-3-yl)benzonitrile;-   3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoro    methyl)benzonitrile;-   2-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;-   4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;-   4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;-   2-Chloro-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;    and-   2-Chloro-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile.

The invention also relates to pharmaceutical compositions comprising acompound of formula I-IV or any of the structural embodiments describedherein and at least one pharmaceutically acceptable excipient.

The invention also provides a method of modulating an androgen receptorin a cell, comprising the administration of a compound to said cellwherein said compound has structural formula I-IV or any of thestructural embodiments described herein, or a pharmaceuticallyacceptable salt thereof.

This invention provides a method of identifying a compound capable ofmodulating an androgen receptor comprising contacting a cell expressingan androgen receptor with a compound according to formula I-IV, andmonitoring the effect of the compound on the cell.

This invention also provides a method of treating (e.g., preventing, orameliorating the symptoms associated with, or reducing the incidence of,reducing the pathogenesis of, facilitating the recovery from or delayingthe onset of) a disease, syndrome, illness, or symptom associated withinsufficient androgen levels in a mammal in need thereof, wherein saidmethod comprises the administration to said mammal of an effectiveamount of a compound of formula I-IV, or any one of the structuralembodiments described herein or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition comprising a compound offormula I-IV, or one of the structural embodiments described herein, ora pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable excipient. In a particular embodiment, the mammal is a human.

In some embodiments, this invention provides a method of treating (e.g.,preventing, or ameliorating the symptoms associated with, or reducingthe incidence of, reducing the pathogenesis of, facilitating therecovery from or delaying the onset of) sarcopenia, frailty, multiplesclerosis, osteoporosis, anemia, cognitive impairment, cachexia,muscular dystrophy, weak appetite, low body weight, anorexia nervosa,acne, seborrhea, polycystic ovarian syndrome, hair loss, AIDs wasting,chronic fatigue syndrome, short stature, low testosterone levels,diminished libido, benign prostate hypertrophy, infertility, erectiledysfunction, vaginal dryness, premenstrual syndrome, postmenopausalsymptoms, female hormone replacement therapy, male hormone replacementtherapy, depression, Type II diabetes, mood disorders, sleep disorders,memory disorders, neurodegenerative disorders, Alzheimer's dementia,attention deficit disorder, senile dementia, coronary artery disease,hirsutism, pain, myalgia, myocardial infarction, stroke, clottingdisorders, thromboembolisms, congestive heart disorder, low insulinsensitivity, low glucose utilization, high blood sugar, organtransplant, metabolic syndrome, diabetes, glucose intolerance,hyperinsulinemia, insulin resistance, tooth injury, tooth disease,periodontal disease, liver disease, thrombocytopenia, fatty liverconditions, endometriosis, hot flushes, hot flashes, vasomotordisturbance, stress disorders, dwarfism, dyslipidemia, cardiovasculardisease, coronary artery disease, renal disease, thin skin disorders,lethargy, osteopenia, dialysis, irritable bowel syndrome, Crohn'sdisease, Paget's disease, osteoarthritis, connective tissue disease ordisorders, injury, burns, trauma, wounds, bone fracture,atherosclerosis, cachexia, cancer cachexia, and obesity, in a mammal inneed thereof comprising the administration to said mammal of aneffective amount of a compound according to a structure of formula I-IVor one of the structural embodiments described herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of structural formula I-IV, or one ofthe structural embodiments described herein including pharmaceuticallyacceptable salts thereof and a pharmaceutically acceptable excipient. Ina particular embodiment, the mammal is a human.

In certain aspects, this invention describes a method of treating (e.g.,preventing, or ameliorating the symptoms associated with, or reducingthe incidence of, reducing the pathogenesis of, facilitating therecovery from or delaying the onset of) prostate cancer, breast cancer,endometrial cancer, hepatocellular cancer, lymphoma, multiple endocrineneoplasia, vaginal cancer, renal cancer, thyroid cancer, testicularcancer, leukemia, and ovarian cancer in a mammal in need thereofcomprising the administration to said mammal of a compound according toa structure of formula I-IV, or one of the structural embodimentsdescribed herein, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising a compound of structural formulaI-IV, or one of the structural embodiments described herein includingpharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable excipient. In a particular embodiment, the mammal is a human.

In the context of this disclosure, the phrase “formula I through IV” ismeant to, in each instant, include compounds of formula I, Ia, Ib, II,IIa, IIb, III, IIIa, IIIb, IV, IVa and IVb

In some embodiments, a process for the preparation of a compound offormula I, Ia and Ib wherein X is O, is described, wherein said processcomprises a process for the preparation of a compound of formula B,comprising:

a) reacting a compound of formula A with a carbonylating reagent

wherein:

R_(x), R_(y), R_(z), R_(a) and R_(b) are each independently as definedfor formula I or any of its related embodiments and;

R₁ is a hydrogen or a suitable carboxylic acid protecting group.

In certain embodiments of this invention, the process of preparing thecompound of formula B is conducted in the presence of a base.

In some embodiments of the processes described herein, R₁ is C₁₋₆alkyl,benzyl or an organosilane.

In certain embodiments of the processes described herein, saidcarbonylating agent is phosgene, triphosgene, N,N′-carbonyldiimadazoleor a dialkylcarbonate.

In certain embodiments, a process for the production of a compound offormula II, IIa and IIb comprising the reaction of a compound of formulaC with a reagent capable of generating a trifluoromethyl anion additionequivalent followed by a proton-donating work-up:

In some embodiments, the trifluoromethyl anion generating equivalentcomprises a trifluoromethylsilane. In certain embodiments, thetrifluoromethyl-containing silane is trimethylsilyltrifluoromethane.

In some embodiments, said trifluoromethyl anion is generated from atrifluoromethylsilane in the presence of a fluoride anion.

DETAILED DESCRIPTION OF THE INVENTION

The term “alkenyl” as used herein refers to a hydrocarbon backboneradical, having the number of carbon atoms falling within the specifiedrange. For example, C₂₋₃alkenyl means that a hydrocarbon radical isattached that may contain anywhere from 2 to 3 carbon atoms with theremaining valence filled in by hydrogen atoms unless specifiedotherwise. The term also includes each permutation as though it wereseparately listed. Thus, C₂₋₃alkenyl includes ethenyl, 1-propenyl and2-propenyl.

The term “alkyl” as used herein refers to both straight and branch chainhydrocarbon radicals, having the number of carbon atoms falling withinthe specified range. For example, C₁₋₄ alkyl means that a hydrocarbonradical is attached that may contain anywhere from 1 to 4 carbon atomswith the remaining valence filled in by hydrogen atoms. The definitionalso includes separately each permutation as though it were separatelylisted. Thus, C₁₋₂alkyl includes methyl and ethyl. The term C₁₋₃ alkylincludes methyl, ethyl, propyl and 2-propyl. The term C₁₋₄ alkylincludes methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyland tert-butyl. The term C₁₋₅alkyl includes methyl, ethyl, 2-propyl,n-butyl, 2-methylbutyl, tert-butyl, n-pentyl, pentan-2-yl, pentan-3-yl,and tert-pentyl, iso-pentyl.

The term “halogen” as used herein refers to a fluorine, chlorine,bromine or iodine radical.

The term “haloalkyl” refers to an alkyl radical wherein said alkylradical is the same as defined for the term “alkyl” except that thealkyl radical additionally has from 1 to 5 halogen atoms attached to thealkyl chain. For example, C₁ haloalkyl includes

—CH₂F, —CHF₂, —CF₃ and the like, C₂ haloalkyl includes —CH₂F, CHF₂, CF₃,—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CF₂CHF₂, —CF₂CF₃ and the like.C₁₋₃haloalkyl is defined to include —CH₂F, —CHF₂, —CF₃, —CH₂CF₃,—CHFCF₃, —CF₂CF₃, —CHClCH₃, —CH₂CH₂Cl, —CH₂CH₂CF₃, and the like. C₁₋₄haloalkyl is defined to include —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CHFCF₃,—CF₂CF₃, —CHClCH₃, —CH₂CH₂Cl, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, CHClCF₂CH₂CH₃,CF₂CH₂CH₂CHF₂, CH₂CH₂CH₂CH₂F, CH₂CH₂CH₂CH₂Cl, and the like,

The term “hydroxyalkyl” refers to an alkyl radical wherein said alkylradical is the same as defined for the term “alkyl” except that thealkyl radical additionally has from 1 or 2 hydroxyl groups attached tothe alkyl chain. For example, C₂₋₄ hydroxyalkyl includes 2-hydroxyethyl,2-hydroxypropyl, 2,4-dihydroxybutyl and the like.

The term “5-member heteroaryl” refers to a heteroaryl ring systemradical wherein said heteroaryl contains at least one heteroatomselected from the groups consisting of N, O and S and up to 3 additionalheteroatoms selected from the group consisting of N, O and S. If nototherwise defined, the 5-member rings system is optionally substitutedwith 1-2 substituents selected from halogen, C₁₋₂alkyl, C₁₋₂ haloalkyl,or CN. The points of attachment of the optional substituent(s) as wellas the rest of the molecule maybe selected from any position whereinthere is an open valence. Some examples of 5-member heteroaryls include:

The term “metabolically labile group” refers to a group that some timeafter administration to an organism, is metabolized in such a way thatthe metabolically labile group becomes hydrogen. Many metabolicprocesses exist in organism whereby a chemical group is removed from therest of the molecule. These metabolic processes include the actions ofenzymes wherein esters can be hydrolytically removed at acceleratedrates or alkyl groups or other functionalities that can be oxidized byvarious metabolizing enzymes leading to the ultimate removal of themetabolically labile group and its replacement by hydrogen. In thecontext of this invention, the metabolically labile group is attached toan oxygen so that when that group is metabolically removed within thetarget organism, it is eventually replaced by a hydrogen at some pointin the metabolic scheme. The metabolism referred to here is typicallyenzyme assisted but does not have to be so. Therefore, the metabolicallylabile group can be removed chemically provided that chemical removaloccurs after administration to an organism. For example, certainmetabolically labile groups might be removed by simple chemicalhydrolysis in the stomach, gut or blood. Metabolically labile groupsrelate to the concept of prodrugs for which those of ordinary skill inthe art appreciate are well-known for secondary alcohols. Thesemetabolically labile groups include esters, carbonates, carbamates,simple alkyl groups, phosphates, phosphites, sulfites, sulfates and thelike. In certain embodiments of this invention, the organism referred tois a mammal. In some embodiments, the mammal is a human.

The compounds of this invention may be present as solids and when sopresent, may be in an amorphous form or they may be crystalline. Whenthe compounds of this invention are in the crystalline form, they mightbe present as a single polymorph or a mixture of polymorphs or even as amixture of amorphous material together with one or more distinctpolymorphs—the invention is not limited according to any particularsolid or liquid state form.

The compounds of this invention contain at least one stereocenter andtherefore, exist in various stereoisomeric forms. Stereoisomers arecompounds which differ only in their spatial arrangement. Enantiomersare pairs of stereoisomers whose mirror images are not superimposable,most commonly because they contain an asymmetrically substituted carbonatom that acts as a chiral center. “Enantiomer” means one of a pair ofmolecules that are mirror images of each other and are notsuperimposable. Diastereomers are stereoisomers that are not related asmirror images, most commonly because they contain two or moreasymmetrically substituted carbon atoms. “R” and “S” represent theconfiguration of substituents around one or more chiral carbon atoms.Thus, “R” and “S” denote the relative configurations of substituentsaround one or more chiral carbon atoms. When the stereochemistry of adisclosed compound is named or depicted by structure, the named ordepicted stereoisomer is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99%or 99.9% by weight pure relative to the other stereoisomers. When asingle enantiomer is named or depicted by structure, the depicted ornamed enantiomer is at least 50%, 60%, 70%, 80%, 90%, 95%, 98%, 99% or99.9% by weight optically pure. Percent optical purity by weight is theratio of the weight of the enantiomer over the weight of the enantiomerplus the weight of its optical isomer.

The compounds of the invention may be prepared as individual isomers byincorporating or starting with a specific isomer, isomer-specificsynthesis, separation of diastereomers or resolution from an isomericmixture. Conventional resolution techniques include forming the salt ofa free base of each isomer of an isomeric pair using an optically activeacid (followed by fractional crystallization and regeneration of thefree base), forming the salt of the acid form of each isomer of anisomeric pair using an optically active amine (followed by fractionalcrystallization and regeneration of the free acid), forming an ester oramide of each of the isomers of an isomeric pair using an optically pureacid, amine or alcohol (followed by chromatographic separation andremoval of the chiral auxiliary), or resolving an isomeric mixture ofeither a starting material or a final product using various well knownchromatographic methods.

Where compounds of this invention include one or more basic sites suchas amines, acid addition salts can be made and this invention includessuch acid addition salts. Some representative (non-limiting) acidaddition salts include hydrochloride, hydrobromide, hydroiodide,acetate, benzenesulfonate, mesylate, besylate, benzoate, tosylate,citrate, tartrate, sulfate, bisulfate, lactate, maleate, mandelate,valerate, laurate, caprylate, propionate, succinate, phosphate,salicylate, napsylate, nitrate, tannate, resorcinate and the like,including multiprotic salts as well as mixtures of the acid additionsalts. In cases where an amine is present, this invention also embracesquaternized ammonium salts of those amines. It should be appreciatedthat N-oxides of amines are also embraced within the definition of thecompounds of this invention. Likewise, where compounds of this inventioninclude one or more acid sites such as carboxylic acids, phenols and thelike, basic addition salts can be made and this invention includes suchbasic addition salts. For example, some representative (non-limiting)acidic compounds of this invention may be present as their lithium,sodium, potassium, ammonium, trialkyammonium, calcium, magnesium, bariumand the like.

The compounds of this invention can also be present as solvates and suchsolvates are embraced within the scope of this invention even where notexplicitly described. Such solvates are preferably hydrates but can besolvates comprised of other solvents, preferably where those solventsare considered to be non-toxic or at least acceptable for administrationto mammals, preferably humans. The solvates can be stoichiometric ornon-stoichiometric, singular or in combination. Some exemplary solvatesinclude water, ethanol, acetic acid and the like.

The therapeutic utility of these compounds includes “treating” a mammal,preferably a human where treating is understood to include treating,preventing, or ameliorating the symptoms associated with, or reducingthe incidence of, reducing the pathogenesis of, facilitating therecovery from or delaying the onset of the syndrome, illness, malady orcondition being considered. The compounds of this invention can also beuseful in states or conditions where no clear deficit, illness or maladyper se is perceived but rather, where a preferred condition, sensation,performance, capability or state is obtainable through therapeuticintervention with a compound of this invention.

The compounds of this invention, when used as therapeutics can beadministered by any method known to one of skill in the art such asorally, bucally, intravenously, subcutaneously, intramuscularly,transdermally, intradermally, intravascularly, intranasally,sublingually, intracranially, rectally, intratumorally, intravaginally,intraperitonealy, pulmonary, ocularly and intratumorally.

As used herein, the term “effective amount” refers to an amount which,when administered in a proper dosing regimen, is sufficient to treat(therapeutically or prophylactically) the target disorder. For example,and effective amount is sufficient to reduce or ameliorate the severity,duration or progression of the disorder being treated, prevent theadvancement of the disorder being treated, cause the regression of thedisorder being treated, or enhance or improve the prophylactic ortherapeutic effect(s) of another therapy.

When administered, the compounds and compositions of this inventionmaybe given once daily or with multiple daily doses such as twice perday, three times per day and four times per day.

In one embodiment of this invention, the compound is administered orallywhere it can be formulated for solid dosage administration or liquiddosage administration. Solid dosage administration can be in the form ofa tablet, granule, capsule, pill, pellet, powder and the like. Liquiddosage formulations include syrups, solutions, gels, suspensions,elixirs, emulsions, colloids, oils, and the like.

As mentioned previously, the compounds of this invention may be solidsand when present as solids, they maybe of defined particle size. Wherethe compound of this invention is not particularly water soluble, it issometimes preferable to administer the compound with a certain particlesize—a particle size with a preferred range where the average meanparticle size diameter is under 100 microns, or 75 microns, or 50microns, or 35 microns, or 10 microns or 5 microns.

Solid dosage formulations will comprise at least one compound of thisinvention together with one or more pharmaceutical excipients. Thoseexcipients are known to one of skill in the art and include, by way ofnon-limiting example diluents (monosaccharides, disaccharides andpolyhydric alcohols including starch, mannitol, dextrose, sucrose,microcrystalline cellulose, maltodextrin, sorbitol, xylitol, fructoseand the like), binders (starch, gelatin, natural sugars, gums, waxes andthe like), disintegrants (alginic acid, carboxymethylcellulose (calciumor sodium), cellulose, crocarmellose, crospovidone, microcrystallinecellulose, sodium starch glycolate, agar and the like), acidic or basicbuffering agents (citrates, phoshphates, gluconates, acetates,carbonates, bicarbonates and the like), chelating agents (edetic acid,edetate calcium, edetate disodium and the like), preservatives (benzoicacid, chlorhexidine gluconate, potassium benzoate, potassium sorbate,sorbic acid, sodium benzoate and the like), glidants and lubricants(calcium stearate, oils, magnesium stearate, magnesium trisilicate,sodium fumarate, colloidal silica, zinc stearate, sodium oleate, stearicacid, and the like), antioxidants and/or preservatives (tocopherols,ascorabtes, phenols, and the like) and acidifying agents (citric acid,fumaric acid, malic acid, tartaric acid and the like) as well ascoloring agents, coating agents, flavoring agents, suspending agents,dessicants, humectants and other excipients known to those of skill inthe art.

The solid dosage formulations of this invention can be prepared indifferent forms including most commonly, tablets and capsules. Thetablets can be formulated by a wide variety of methods known to one ofskill in the art including, for example, preparing a dry powder mixtureof the drug substance in combination with one or more of the excipientsgranulating the mixture and pressing to together into a tablet andoptionally coating the tablet with an enteric or non-enteric coating.The final coat typically includes a light protective pigment such astitanium oxide and a shellac or wax to keep the tablet dry and stable.While not intending to be limited by theory or example, in someinstances it might be preferred to prepare the tablets by wetgranulating the drug with one or more of the excipients and thenextruding the granulated material.

The solid dosage forms of this invention also include capsules whereinthe drug is enclosed inside the capsule either as a powder together withoptional excipients or as granules containing usually including one ormore excipients together with the drug and wherein the granule in turncan be optionally coated, for example, enterically or non-enterically.

In certain embodiments of this invention, the solid dosage formulationsof this invention are formulated in a sustained release formulation.Such formulations are known to those of skill in the art and generallyrely on the co-formulation of the drug with one or more matrix formingsubstances that slow the release of the androgen receptor modulator thusextending the compound's lifetime in the digestive track and therebyextend the compounds half-life. Some non-limiting matrix formingsubstances include hydroxypropyl methylcellulose, carbopol, sodiumcarboxymethylcellulose and the like.

In some embodiments of this invention, the compounds are formulated fordelivery other than via a solid oral dosage form. For example, incertain instances it might be preferable to deliver a compound of thisinvention by a pulmonary route. A pulmonary route of administrationtypically means that the compound of this invention is inhaled into thelung where it is absorbed into the circulation. Such a route ofadministration has the advantage of avoiding a first pass liver effectthereby possibly increasing bioavailability as well as decreasing oreliminating undesirable androgen agonist effects on the liver such asincreasing liver enzymes and/or decreasing HDL. Formulating a compoundof the invention for pulmonary delivery can be accomplished bymicronizing the compound of the invention to a very fine size particle,typically with a mean average diameter of less than 20 microns, or lessthan 10 microns or between 2 and 5 microns. The powder may then beinhaled by itself or more likely mixed with one or more excipients suchas lactose or maltose. The powder can then be inhaled in a dry powderinhaling device either once or multiple times per day depending on theparticular compound and the patients need. Other types of pulmonarydosage forms are also embraced by this invention. In an alternative tothe dry powder delivery, the compound of this invention may be suspendedin an aerosolizing medium and inhaled as a suspension through a meterdosed inhaler or a nebulizer.

The compounds of this invention can be formulated for transdermaldelivery. Effective advantage of these compounds can be taken through awide variety of transdermal options. For example, the compounds of thisinvention maybe formulated for passive diffusion patches where they arepreferably embedded in a matrix that allows for slow diffusion of thecompound into the treated subject's circulation. For this purpose, thecompound is preferably dissolved or suspended in solvents including byway of non-limiting examples one or more of ethanol, water, propyleneglycol, and Klucel HF. In some instances, a polymer matrix (e.g.acrylate adhesive) will comprise the bulk of the transdermalformulation. In some instances, the transdermal formulations maybedesigned to be compatible with alternate transdermal deliverytechnologies. For example, some transdermal technologies achieve greaterand/or more consistent delivery by creating micropores in the skin usingradio frequency, heat, ultrasound or electricity. In some cases, thecompounds of this invention can be used with microneedle technologywherein the compound is loaded into or onto very small needles which donot need to penetrate the dermis to be effective.

The compounds of this invention may be employed alone or in combinationwith other therapeutic agents. By way of non-limiting example, thecompounds of this invention can be used in combination withanti-lipidemics (statins, fibrates, omega-3 oils, niacinates and thelike), bone anti-resorptives (bisphosphonates, estrogens, selectiveestrogen receptor modulators (SERMs), calcitonin, and the like), boneanabolic agents (PTH and fragments e.g teriparatide, PTHRP and analoguese.g. BaO58), anti-diabetics (e.g. insulin sensitizers, glucoseabsorption and synthesis inhibitors (e.g. metformin)), anti-anxietyagents, antidepressants, anti-obesity agents, contraceptive agents,anti-cancer agents, PPARγ agonists (e.g. pioglitazone), and the like.When used in combination, the compounds of this invention may beco-formulated or co-administered wherein said co-administration does notrequire dosing at exactly the same time but rather indicates that thepatient is undergoing treatment with one or more of the additionalagents during the timeframe of treatment with the selective androgenmodulators of this invention. Thus, the additional drug(s) forcombination treatment can be administered concomitantly, sequentially orseparately from the compounds of this invention.

The compounds of this invention may be administered according todifferent dosage scheduling and the dosage may be adjusted as deemednecessary by the subject or preferably by the subject in consultationwith a qualified practitioner of medicine. Dosing of the compounds ofthis invention can take place by multiple routes and consequently, thedosing schedule and amounts are dependent not only on the particularsubject's weight, sex, age, therapy contemplated, etc but also by theroute of the drug chosen.

By way of non-limiting example, the compounds of this invention may beconsidered for dosing by the oral route in a once daily, twice daily,three times daily or more than three times per day depending on theparticular needs of that subject, the formulation of the drug, etc. Thedosage will typically be from about 0.01 mg to 500 mg of drug per dailydosage, for example from about 0.1 mg to about 10 mg, such as from about0.1 mg to about 3 mg, or from about 0.1 mg to about 250 mg of drug perdaily dosage, or from about 1 mg to about 150 mg of drug per dailydosage, or from about 5 mg to about 100 mg of drug per daily dosage.

It is understood that the amount of compound dosed per day can beadministered every day, every other day, every 2 days, every 3 days,every 4 days, every 5 days, etc. For example, with every other dayadministration, a 5 mg per day dose can be initiated on Monday with afirst subsequent 5 mg per day dose administered on Wednesday, a secondsubsequent 5 mg per day dose administered on Friday, etc. In oneembodiment, a compound of this invention is dosed once every seven days.

The compounds of this invention can also be dosed on a monthly basismeaning that administration is done once per month. In addition, thecompounds of this invention can be dosed on a weekly basis (once aweek), every other week, every three weeks or every four weeks for asingle day or multiple days.

It should be appreciated that the dose interval for the compounds ofthis invention can be adjusted according to the particular compoundused, its dosage, the indication being treated and the patient and/orphysician's judgment.

The compounds of this invention can also be dosed on an as needed or“pro re nata” “prn” schedule, and “on demand”. In this type of dosing,the compounds of this invention are administered in a therapeuticallyeffective dose at some time prior to commencement of an activity whereinthe therapeutic effect of the compounds of this invention is desirable.Administration can be immediately prior to such an activity, includingabout 0 minutes, about 10 minutes, about 20 minutes, about 30 minutes,about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, orabout 10 hours prior to such an activity, depending on the formulation.

The compounds of this invention can be prepared by a variety ofsynthetic routes and techniques known to those of skill in the art. Theprocesses disclosed herein should not be construed as limiting theexamples or scope of the invention in any way but rather are provided asjust some of the representative ways that the compounds of thisinvention can be or were prepared.

In some cases, protective groups are employed in the synthesis of thecompounds of this invention and it should be appreciated that there area diverse array of protective groups and strategies that can be employedin organic synthesis (T. W. Green and P. G. M. Wuts (2006) Greene'sProtective Groups in Organic Synthesis, herein incorporated by referencein its entirety) and that where a protective group is referred togenerically, any appropriate protective group should be considered.

In some instances, leaving groups are employed in the synthesis ofcompounds of this invention. Where a specific leaving group is referredto, it should be appreciated that other leaving groups might also beused. Leaving groups typically include those groups that can stabilizean anion. In the case of nucleophilic aromatic substitutions, theleaving group may be an anion or a neutrally charged group. In somecases, the leaving group for nucleophilic aromatic substitution may be agroup that is not typically considered to be a stabilized anion (e.g.fluoride or hydride). While not intending to be bound by theory or theexamples, some typical nucleophilic leaving groups include halogens,sulfonates (O-mesylates, O-tosylates, etc), hydrides, quaternizedamines, nitro, and the like. Additional discussion and examples can befound in leading textbooks on organic chemistry including, for example,March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5^(th) Edition, which is herein incorporated in its entirety.

Assignment of stereochemistry—The examples of this invention describedherein have at least two stereocenters. Due to the nature of thechemical syntheses used for the preparation of the specific examples ofthis invention, a set of diastereomers was obtained for each compoundsynthesized. It was observed that these diastereomers separated fairlyreadily by silica gel chromatography using EtOAc and hexanes.

The absolute stereochemistry of the diastereomers were assigned byanalogy to the single X-Ray crystal solution obtained for onediastereomer (the compound of Example 20) from one of the diastereomericpairs (compounds of Examples 19 and 20).

Example 20 was the less polar isomer and was shown to have the structureshown, having 4(R) side chain stereochemistry in accordance with theCahn-Ingold-Prelog priority rules. Since Example 20 had the 4(R) sidechain stereochemistry, Example 19 was assigned as the other diastereomerwith 4(S) stereochemistry in accordance with the Cahn-Ingold-Prelogpriority rules. In addition, Example 20 also demonstrated lower androgenreceptor binding affinity than Example 19:

Example 20

-   -   Less Polar Isomer (SiO₂50% EtOAc/hexanes; R_(f)=0.5)    -   (Structure established by single crystal X-Ray)    -   AR binding IC₅₀=72 nM

Example 19

-   -   More Polar Isomer (SiO₂50% EtOAc/hexanes; R_(f)=0.2)    -   AR binding IC₅₀=4 nM

For all of the specific examples of this invention, each diastereomericpair included one isomer that was clearly less polar than the other(EtOAc/hexanes on silica gel thin layer chromatography). The less polarisomer also had weaker affinity for the androgen receptor as measured byassays described herein. Accordingly, the less polar isomer which wasalso, in every case, the less active isomer was assigned the same 4(R)side chain stereochemistry as the compound of Example 20.

Despite the efforts to determine the actual structural formula for eachpair of diatereomers as described above, it is possible that one or morepairs could be inadvertently assigned the wrong absolutestereochemistry. One of ordinary skill in the art appreciates that bothpossible diastereomers can be produced after addition of the CF₃ groupand that these diastereomers can be separated. One diastereomer willhave from slightly better to significantly better affinity for theandrogen receptor than the other, though in many cases both havedemonstrable activity in in vitro binding and/or in vivo experimentssuch as the rat Herschberger assay. Both isomers are included undervarious embodiments of this invention.

EXPERIMENTAL PROCEDURES Examples 1 and 2

4-bromo-2-(trifluoromethyl)benzonitrile

To a solution of 4-amino-2-(trifluoromethyl)benzonitrile (la) (5.0 g,26.9 mmol) in CH₃CN (50 mL), cooled to 0° C., Isoamyl nitrite (6 mL,40.9 mmol) was added and stirred for 30 min. Then CuBr₂ (7.1 g, 32.0mmol) was added portion wise to the reaction mixture maintaining thetemperature at 0° C. The reaction mixture was slowly warmed to roomtemperature and stirred for further 4 h. After completion of reaction(by TLC), the reaction mixture was poured into saturated NaCl solutionand extracted with EtOAc (3×70 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to provide thecrude residue which was purified by column chromatography to afford thebromo 1b (5 g, 74%) as a syrup.

TLC: 30% EtOAc/Hexane (R_(f): 0.8)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 7.95 (s, 1H), 7.85 (d, J=8.5 Hz, 1H),7.71 (d, J=8.5 Hz, 1H).

(R)-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile(1c)

To a solution of bromo 1b (3 g, 12.0 mmol) dissolved in 1,4-Dioxane (40mL), (R)-5-((trityloxy)methyl)pyrrolidin-2-one 1c (4 g, 11.2 mmol) wasadded at room temperature followed by Cs₂CO₃ (4.2 g, 13 mmol) and Argongas was purged for 30 min. To the reaction mixture Pd₂(dba)₃ (0.5 g,0.55 mmol) and Xanthphos (0.8 g, 1.38 mmol) were added at roomtemperature. The resulting reaction mixture was then heated to 100° C.for 16 h. After completion of the reaction (by TLC), the reactionmixture was filtered through celite bed. The celite bed was washed withEtOAc (5 mL) and the filtrates were combined, dried over Na₂SO₄ andconcentrated under reduced pressure to give the crude compound. Thecrude material was purified by column chromatography to furnish theTrityl ether 1d (3.1 g, 50%) as off white solid.

TLC: 40% EtOAc/Hexane (R_(f): 0.3)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 8.30 (s, 1H), 8.09 (d, J=9.0 Hz, 1H),7.88 (t, J=8.5 Hz, 1H), 7.22-7.19 (m, 10H), 7.15-7.14 (m, 5H), 4.81 (d,J=6.0 Hz, 1H), 3.21 (dd, J=10.5 Hz, 3.0 Hz, 1H), 3.13 (dd, J=10.5 Hz,3.5 Hz, 1H), 2.83-2.76 (m, 1H), 2.56-2.54 (m, 1H), 2.36-2.25 (m, 1H),2.03-1.99 (m, 1H).

Mass (ESI): 527.2 [M⁺+1].

(R)-4-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile1e

To a solution of(R)-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1d (3 g, 5.69 mmol) in 1,4-dioxane (30 mL), cooledto 0° C., 2M HCl in dioxane (30 mL) was added. The reaction mixture wasthen warmed up to room temperature and stirred for 16 h. Aftercompletion (by TLC), the reaction mixture was diluted with H₂O (20 mL)and extracted with EtOAc (3×75 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure. The crudematerial was purified by column chromatography to afford the alcohol 1e(1.6 g, 93%) as a white solid.

TLC: 50% EtOAc/Hexane (R_(f): 0.2)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 8.48 (s, 1H), 8.16 (d, J=8.5 Hz, 1H),7.98 (dd, J=8.5 Hz, 2.0 Hz, 1H), 4.93 (t, J=5.5 Hz, 1H), 4.63-4.60 (dd,J=8.5, 4.0 Hz, 1H), 3.58-3.53 (m, 1H), 3.48-3.44 (m, 1H), 2.75-2.68 (m,1H), 2.46-2.40 (m, 1H), 2.25-2.17 (m, 1H), 2.05-1.99 (m, 1H).

4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile(Example 1) &4-((R)-2-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile(Example 2)

Examples 1 and 2

To a solution of(R)-4-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile (1e) (1.0 g, 3.53 mmol) in CH₂Cl₂ (50 mL), cooled to0° C., Dess-Martin periodinane (2.9 g, 7.0 mmol) was added. The reactionmixture was slowly warmed to room temperature, stirred for 6 h andquenched with saturated NaHCO₃ solution (50 mL) and extracted with EtOAc(3×75 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to provide the aldehyde 1f (1.0 g,crude) which was carried forward to the next step without anypurification.

TLC: 50% EtOAc/Hexane (R_(f): 0.5)

The crude aldehyde 1f (1.0 g, 3.56 mmol) was dissolved in dry THF (50mL), cooled to 0° C., and CsF (0.6 g, 3.97 mmol) followed by CF₃TMS (6mL, 35.0 mmol) was added and stirred for 6 h. After completion ofreaction (by TLC), the reaction mixture was quenched with aqueous NH₄Cland extracted with EtOAc (3×75 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to furnish thecrude silyl ether 1g (1.2 g) as a mixture of diastereomers. The crudematerial was used for the next step without purification.

TLC: 50% EtOAc/Hexane R_(f): (0.7 & 0.8)

The crude silyl ether 1g (1.2 g, 2.83 mmol) was taken in THF (50 mL) andKOH (0.46 g, 8.36 mmol) dissolved in H₂O (50 mL) was added at 0° C. andstirred for 1 h. After completion of reaction (by TLC), the reactionmixture was diluted with H₂O (20 mL) and extracted with EtOAc (3×75 mL).The combined organic extracts were dried over Na₂SO₄ and concentratedunder reduced pressure to give the crude residue which was purified bycolumn chromatography to afford Example 1 (0.1 g) and Example 2 (0.4 g)both as white solids.

TLC: 50% EtOAc/Hexane R_(f): (0.2 (Example 1) & 0.4 (Example 2)

Example 1

¹H NMR (500 MHz, CDCl₃, δ in ppm) (Example 1): 8.22 (d, J=1.5 Hz, 1H),8.16 (t, J=8.5 Hz, 1H), 8.02 (dd, J=8.5 Hz, 2.0 Hz, 1H), 6.69 (d, J=6.5Hz, 1H), 4.97 (t, J=6.0 Hz, 1H), 4.31-4.27 (m, 1H), 2.81-2.76 (m, 1H),2.45-2.35 (m, 2H), 2.07-2.03 (m, 1H).

Mass (ESI): 351.0 [M⁺−1]

HPLC purity: 98.26%

Example 2

¹H NMR (500 MHz, CDCl₃, δ in ppm): 8.29 (s, 1H), 8.24 (d, J=8.0 Hz, 1H),7.93 (d, J=9.0 Hz, 1H), 6.74 (d, J=6.5 Hz, 1H), 4.98 (d, J=5.5 Hz, 1H),4.09 (t, J=7.5 Hz, 1H), 2.70-2.65 (m, 1H), 2.50-2.48 (m, 1H), 2.24-2.19(m, 2H).

Mass (ESI): 351.0 [M⁺−1]

HPLC purity: 97.1%

Example 3 & Example 4

N-(4-chloro-3-(trifluoromethyl)phenyl)pivalamide (3b)

To a solution of 4-chloro-3-(trifluoromethyl) aniline (3a) (0.5 g, 2.55mmol) in dry THF (8 mL), cooled to 0° C., Et₃N (0.4 mL, 2.76 mmol)followed by PivCl (0.34 mL, 2.8 mmol) were added. The reaction mixturewas stirred at room temperature for 4 h. After completion of reaction(by TLC), the reaction mixture was diluted with water (20 mL) andextracted with EtOAc (3×15 mL). The combined organic extracts werewashed with water (30 mL). The organic layer was separated dried overNa₂SO₄ and concentrated under reduced pressure to give the crudematerial which was triturated with n-hexane to afford the desired amide3b (0.45 g, 60%) as a white solid.

TLC: 35% EtOAc/Hexane (R_(f): 0.4)

¹H NMR (200 MHz, CDCl₃, δ in ppm): 7.87 (d, J=2.6 Hz, 1H), 7.74 (dd,J=8.8 Hz, 2.6 Hz, 1H), 7.44 (d, J=8.6 Hz, 2H), 1.33 (s, 9H).

Mass (ESI): 280.1 [M⁺]

N-(4-chloro-2-methyl-3-(trifluoromethyl)phenyl)pivalamide (3c)

N-(4-chloro-3-(trifluoromethyl)phenyl)pivalamide (3b) (3 g, 10.7 mmol)was dissolved in dry THF (30 mL), cooled to 0° C., and n-BuLi (15.6 mL,25.7 mmol) was added. After 3 h, a solution of MeI (0.66 mL, 10.56 mmol)in THF (7 mL) was added to the reaction mixture maintaining thetemperature at 0° C. and stirred for further 3 h. and quenched withaqueous NH₄Cl solution. The reaction mixture was extracted with EtOAc(3×30 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to give the crude material which waspurified by column chromatography to affordN-(4-chloro-2-methyl-3-(trifluoromethyl)phenyl)pivalamide (3c) (2.0 g,64%) as off white solid.

TLC: 40% EtOAc/Hexane (R_(f): 0.5)

¹H NMR (200 MHz, CDCl₃, δ in ppm): 7.76 (d, J=8.8 Hz, 1H), 7.35 (d,J=8.6 Hz, 1H), 7.21 (br s, 1H), 2.38-2.34 (m, 3H), 1.35 (s, 9H).

Mass (ESI): 293.9 [M⁺+1]

N-(4-cyano-2-methyl-3-(trifluoromethyl)phenyl)pivalamide (3d)

To a solution of N-(4-chloro-2-methyl-3-(trifluoromethyl)phenyl)pivalamide (3c) (0.4 g, 1.36 mmol) in NMP (5 mL) CuCN (0.3 g, 34.0 mmol)was added at room temperature under nitrogen atmosphere and heated to220° C. for 36 h. The reaction mixture was slowly brought to roomtemperature, diluted with water (10 mL) and extracted with EtOAc (3×15mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to give the crude compound which waspurified by column chromatography to furnish the nitrile 3d (0.2 g, 52%)as a white solid.

TLC: 30% EtOAc/Hexane (R_(f): 0.5)

¹H NMR (200 MHz, CDCl₃, δ in ppm): 8.43 (d, J=8.4 Hz, 1H), 7.69 (d,J=8.4 Hz, 1H), 7.51 (br s, 1H), 2.39 (d, J=1.2 Hz, 3H), 1.36 (s, 9H).

Mass (ESI): 284.9 [M⁺+1]

4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (3 e)

N-(4-cyano-2-methyl-3-(trifluoromethyl)phenyl)pivalamide (3d) (1.5 g,5.28 mmol) was taken in EtOH/HCl (30 mL, 1:1) and heated to 80° C. for12 h. The reaction was slowly brought to room temperature and pouredinto ice cold water (30 mL) during which white solid precipitated whichwas filtered. The solid was washed with hexane (3×20 mL) and dried undervacuum to provide the amine 3e (0.9 g, 90%) as a white solid.

TLC: 40% EtOAc/Hexane (R_(f): 0.3)

¹H NMR (200 MHz, DMSO-d₆, δ in ppm): 7.51 (d, J=8.2 Hz, 1H), 6.91 (d,J=8.6 Hz, 1H), 6.45 (br s, 2H), 2.15-2.12 (m, 3H).

Mass (ESI): 198.9 [M⁺-]

4-bromo-3-methyl-2-(trifluoromethyl)benzonitrile (3f)

To a solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (3e)(0.8 g, 4.0 mmol) in water (2 mL), cooled to 00° C., 48% aqueous HBr (10mL, 18.5 mmol) was added followed by NaNO₂ (0.33 g, 4.8 mmol) taken inwater (2 mL) and stirred for 10 min. To the reaction mixture a solutionof CuBr (2.7 g, 18.8 mmol) in HBr (10 mL) was added at 0° C. and slowlywarmed to room temperature and then heated to 50° C. for 1 h. Thereaction mixture was brought to room temperature, diluted with water (50mL) and extracted with EtOAc (3×20 mL). The combined organic extractswere washed with water (2×20 mL), dried over Na₂SO₄ and concentratedunder reduced pressure to give the crude compound which was purified bycolumn chromatography to provide the bromo 3f (0.6 g, 60%) as a tancolored solid.

TLC: 10% EtOAc/Hexane R_(f): (0.6)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 7.88 (d, J=9.0 Hz, 1H), 7.52 (d,J=8.0 Hz, 1H), 2.62 (s, 3H).

(R)-3-methyl-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile(3h)

The bromo-compound 3f (0.5 g, 1.89 mmol) was dissolved in 1,4-dioxane(10 mL) and (R)-5-((trityloxy)methyl)pyrrolidin-2-one (3g) (0.54 g, 1.51mmol) was added followed by Cs₂CO₃ (1.2 g, 3.78 mmol) at roomtemperature. The reaction mixture was degassed with Argon gas for 30min, Pd₂(dba)₃ (0.17 g, 0.18 mmol) and Xanthphos (0.21 g, 0.37 mmol)were added and heated to 80° C. for 12 h. After completion of reaction(by TLC), the reaction mixture was diluted with water (20 mL), filteredthrough celite bed and the filtrate was washed with water (2×20 mL). Theorganic layer was separated, dried over Na₂SO₄ and concentrated underreduced pressure to give the crude compound which was purified by columnchromatography to afford(R)-3-methyl-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile(3h) (0.26 g, 26%) as a brown solid.

TLC: 50% EtOAc/Hexane R_(f): (0.2)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.07 (d, J=7.5 Hz, 1H), 7.87 (d,J=8.0 Hz, 1H), 7.23 (s, 10H), 7.02 (s, 5H), 4.62 (br s, 1H), 3.09-2.07(m, 1H), 2.99-2.97 (m, 1H), 2.46-2.45 (m, 1H), 2.29 (br s, 2H), 2.07 (s,3H), 1.99-1.95 (m, 1H).

Mass (ESI): 541.3 [M⁺+1]

(R)-4-(2-(hydroxymethyl)-5-oxopyrrolidin-1-yl)-3-methyl-2-(trifluoromethyl)benzonitrile(3i)

To a solution of(R)-3-methyl-4-(2-oxo-5-((trityloxy)methyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile(3h) (0.48 g, 0.93 mmol) in 1,4-dioxane (15 mL), 2M HCl in 1,4-dioxane(5 mL) was added at 0° C. and stirred for 4 h. After completion ofreaction (by TLC), the reaction mixture was diluted with water (20 mL)and extracted with EtOAc (2×15 mL). The combined organic extracts werewashed with water (2×30 mL), dried over Na₂SO₄ and concentrated underreduced pressure to obtain the crude compound was purified by columnchromatography to provide the alcohol 3i (0.22 g, 79%) as a white solid.

TLC: 80% EtOAc/Hexane R_(f): (0.2)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.02 (d, J=7.5 Hz, 1H), 7.83 (br s,1H), 4.82 (br s, 1H), 4.34 (br s, 1H), 3.39-3.33 (m, 2H), 2.56-2.53 (m,1H), 2.46-2.41 (m, 1H), 2.31 (s, 3H), 2.28-2.25 (m, 1H), 2.08-2.01 (m,1H).

3-methyl-4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile3 &3-methyl-4-((R)-2-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile4

3i to 3j

The alcohol 31 (0.29 g, 0.97 mmol) was dissolved in CH₃CN (10 mL),cooled to 0° C., and Dess-Martin periodinane (0.62 g, 1.46 mmol) wasadded and stirred for 3 h. After completion of reaction (by TLC), thereaction mixture was quenched with aqueous NaHCO₃ solution (20 mL) andextracted with EtOAc (2×15 mL). The combined organic extracts werewashed with water (2×20 mL), separated, dried over Na₂SO₄ andconcentrated under reduced pressure to furnish the aldehyde 3j (0.22 g,crude) as a white solid which was taken to the next step withoutpurification.

TLC: 10% MeOH/CH₂Cl₂ R_(f): (0.5)

3j to 3k

The aldehyde 3j (0.22 g, 0.87 mmol) was dissolved in dry THF (10 mL),cooled to 0° C., CsF (0.13 g, 0.87 mmol) followed by CF₃TMS (1.2 mL,8.43 mmol) were added and stirred for 1 h. After completion of reaction(by TLC), the reaction mixture was quenched with aqueous NH₄Cl solutionand extracted with EtOAc (2×20 mL). The combined organic extracts werewashed with water (2×10 mL), separated, dried over Na₂SO₄ andconcentrated under reduced pressure to give the crude silyl ether 3k asa mixture of diastereomers (0.23 g, crude). The crude material wascarried further without purification.

TLC: 60% EtOAc/Hexane R_(f): (0.4 & 0.6)

3k to Example 3 and 4

The silyl ether 3k (0.23 g, 0.52 mmol) was taken in dry THF (5 mL),cooled to 0° C., and a solution of KOH (0.088 g, 1.57 mmol) in H₂O (2mL) was slowly added and stirred for 1 h. After completion of reaction(by TLC), the reaction mixture was diluted with H₂O (20 mL) andextracted with EtOAc (3×15 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated under reduced pressure to give the cruderesidue which was purified by column chromatography to afford Example 3(0.022 g) and Example 4 (0.018 g) both as white solids.

TLC: 80% EtOAc/Hexane R_(f): (0.2 Example 3 & 0.6 Example 4).

Example 3

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.99 (d, J=8.0 Hz, 1H), 7.90 (d,J=8.0 Hz, 1H), 6.64 (d, J=6.0 Hz, 1H), 4.60 (m, 1H), 4.27-4.26 (m, 1H),2.68-2.64 (m, 1H), 2.50-2.36 (m, 2H), 2.31 (s, 3H), 2.08 (m, 1H).

Mass (ESI): 365.3 [M⁺−1]

HPLC purity: 98.10%

Example 4

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.07 (d, J=8.0 Hz, 1H), 7.93 (d,J=8.0 Hz, 1H), 6.69 (d, J=6.5 Hz, 1H), 4.69 (br s, 1H), 3.91-3.82 (m,1H), 2.36-2.29 (m, 6H), 2.16 (br s, 1H).

Mass (ESI): 365.1 [M⁺−1]

HPLC purity: 96.33%

Examples 5 and 6

5a to 5b 2-Amino-5-nitrobenzenethiol

To a solution of 6-Nitrobenzo[d]thiazole (5a) (10 g, 55.5 mmol) in EtOH(100 mL), Hydrazine hydrate (39 g, 77.9 mmol) was added at roomtemperature under nitrogen atmosphere. The reaction mixture was stirredat room temperature for 4 h. After completion of the reaction (by TLC)the volatiles were removed under reduced pressure, the residue wasneutralized with 1N HCl (100 mL) and extracted with EtOAc (3×150 mL).The combined organic extracts were dried over Na₂SO₄ and concentratedunder reduced pressure to afford 2-Amino-5-nitrobenzenethiol (5b) (7.0g, crude). The crude material was taken to the next step withoutpurification.

TLC: 30% EtOAc/Hexane (R_(f): 0.2)

5b to 5c 6-Nitrobenzo[d][1,2,3]thiadiazole

To a solution of 2-Amino-5-nitrobenzenethiol (5b) (6.0 g, 35.3 mmol) inn-BuOH (30 mL), cooled to 0° C., a solution of Isoamyl nitrite (5.0 mL,37.1 mmol) in n-BuOH (30 mL) was added followed by conc. HCl (5.0 ml).The reaction mixture was warmed to room temperature and stirred for 5 h.To the resulting reaction mixture Acetamide (0.4 ml) was added andstirred for another 30 min at room temperature. After completion ofreaction (by TLC), the reaction mixture was diluted with H₂O (80 mL) andextracted with EtOAc (3×150 mL). The combined organic extracts werewashed with brine solution (100 mL), dried over Na₂SO₄ and concentratedunder reduced pressure to obtain the crude material which was purifiedby column chromatography to afford 6-Nitrobenzo[d][1,2,3]thiadiazole(5c) (3.5 g, 54%) as a yellow solid.

TLC: 30% EtOAc/Hexane (R_(f): 0.8)

¹H NMR (200 MHz, CDCl₃, δ in ppm): 9.05 (d, J=1.8 Hz, 1H), 8.80 (d,J=9.0 Hz, 1H), 8.51 (dd, J=9.2 Hz, 2.2 Hz, 1H).

5c to 5d Benzo[d][1,2,3]thiadiazol-6-amine

6-Nitrobenzo[d][1,2,3]thiadiazole (5c) (4.0 g, 22.1 mmol) was taken incone. HCl (100 mL), cooled to 0° C., and SnCl₂.H₂O (15 g, 66.5 mmol)dissolved in conc. HCl (80 mL) was added. The resulting reaction mixturewas slowly brought to room temperature and stirred for 5 h. Aftercompletion of reaction (by TLC), the reaction mixture was diluted withwater (50 mL), neutralized with saturated NaHCO₃ solution (pH˜8-9) andextracted with EtOAc (3×150 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to give thecrude compound which was purified by column chromatography to furnishthe amine 5d (2.8 g, 82%).

TLC: 30% EtOAc/Hexane (R_(f): 0.2)

¹H NMR (200 MHz, CDCl₃, δ in ppm): 8.34 (d, J=9.0 Hz, 1H), 7.14 (d,J=2.2 Hz, 1H), 6.93 (dd, J=8.8 Hz, 2.0 Hz, 1H), 4.23 (br s, 2H).

Mass (ESI): 152.0 [M⁺+1]

5d to 5e 6-Bromobenzo[d][1,2,3]thiadiazole

To a solution of Benzo[d][1,2,3]thiadiazol-6-amine (5d) (0.5 g, 3.31mmol) in H₂O (10 mL), cooled to 0° C., HBr (13 mL) was added drop-wisefollowed by a solution of NaNO₂ (252 mg, 3.65 mmol) in H₂O (4 mL). After1 h, a solution of CuBr (0.62 g, 4.33 mmol) in HBr (13 mL) was added tothe reaction mixture maintaining the temperature at 0° C. The resultingreaction mixture was heated to 80° C. for 2 h. After completion ofreaction (by TLC), the reaction mixture was diluted with water (30 mL)neutralized with saturated NaHCO₃ solution and extracted with Et₂O (3×35mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to give the crude compound waspurified by column chromatography to give the bromo 5e (0.25 g, 35%).

TLC: 30% EtOAc/Hexane (R_(f): 0.8)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 8.49 (d, J=8.5 Hz, 1H), 8.28 (d,J=1.5 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H).

5e to 5g(R)-1-(benzo[d][1,2,3]thiadiazol-6-yl)-5-(trityloxymethyl)pyrrolidin-2-one

To a solution of 6-Bromobenzo[d][1,2,3]thiadiazole (5e) (175 mg, 0.81mmol) and (R)-5-(trityloxymethyl)pyrrolidin-2-one (5f) (290 mg, 0.81mmol) in 1,4-dioxane (20 mL), Cs₂CO₃ (0.292 g, 0.89 mmol) was added atroom temperature and degassed with Argon for 30 min. To the reactionmixture Pd₂(dba)₃ (0.040 g, 0.04 mmol) and Xanthphos (0.057 g, 0.09mmol) were added at room temperature and heated to 90° C. for 16 h.After completion of reaction (by TLC), the reaction mixture was filteredthrough celite bed and the filtrate was concentrated under reducedpressure to give the crude compound which was purified by columnchromatography to provide the Trityl ether 5g (0.3 g, 75%).

TLC: 50% EtOAc/Hexane R_(f): (0.6)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.64 (d, J=9.0 Hz, 1H), 8.51 (s,1H), 7.95 (d, J=9.5 Hz, 1H), 7.19-7.12 (m, 15H), 4.76-4.74 (m, 1H), 3.22(dd, J=10.0 Hz, 2.5 Hz, 1H), 3.05 (dd, J=10.0 Hz, 3.0 Hz, 1H), 2.80-2.74(m, 1H), 2.57-2.53 (m, 1H), 2.36-2.28 (m, 1H), 1.99 (t, J=10.5 Hz, 1H).

5g to 5h(R)-1-(benzo[d][1,2,3]thiadiazol-6-yl)-5-(hydroxymethyl)pyrrolidin-2-one

To a solution of(R)-1-(benzo[d][1,2,3]thiadiazol-6-yl)-5-(trityloxymethyl)pyrrolidin-2-one(5g) (0.3 g, 0.61 mmol) in dry THF (10 mL), cooled to 0° C., 2M HCltaken in 1,4-dioxane (1 mL) was added. The resulting reaction mixturewas warmed up to room temperature and stirred for 2 h. After completionof reaction (by TLC), the reaction mixture was diluted with water (10mL), basified with saturated NaHCO₃ solution (pH˜8-9) and extracted withEtOAc (3×35 mL). The combined organic extracts were dried over Na₂SO₄and concentrated under reduced pressure to furnish the alcohol 5h (0.12g, 80%) which was taken to the next step without purification.

TLC: 60% EtOAc/Hexane R_(f): (0.2)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.68 (d, J=9.0 Hz, 1H), 8.59 (d,J=1.5 Hz, 1H), 8.03 (dd, J=9.0 Hz, 2.0 Hz, 1H), 4.89 (t, J=5.5 Hz, 1H),4.55-4.54 (m, 1H), 3.57-3.52 (m, 1H), 3.49-3.46 (m, 1H), 2.72-2.65 (m,1H), 2.47-2.41 (m, 1H), 2.29-2.21 (m, 1H), 2.09-2.04 (m, 1H).

Mass (ESI): 249.9 [M⁺+1]

5h to Examples 5 and 6(R)-1-(Benzo[d][1,2,3]thiadiazol-6-yl)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one5(R)-1-(Benzo[d][1,2,3]thiadiazol-6-yl)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one6

5h to 5i

To a solution of alcohol 5h (0.12 g, 0.48 mmol) in dry CH₂Cl₂ (10 mL),cooled to 0° C., Dess-Martin periodinane (0.23 g, 0.54 mmol) was added.The resulting reaction mixture was warmed to room temperature andstirred for 4 h. After completion of reaction (by TLC), the reactionmixture was diluted with water (20 mL) and extracted with CH₂Cl₂ (3×35mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography to provide the aldehyde 51 (0.1 g, 83%).

TLC: 50% EtOAc/Hexane R_(f): (0.6)

5i to 5j

The crude aldehyde 51 (0.15 g, 0.6 mmol) was dissolved in dry THF (10mL), cooled to 0° C., CsF (90 mg, 0.6 mmol) followed by CF₃TMS (0.8 mL,60.0 mmol) were added. The resulting reaction mixture was warmed to roomtemperature and stirred for 1 h. After completion of reaction (by TLC),the reaction mixture was quenched with aqueous NH₄Cl solution (20 mL)and extracted with EtOAc (3×20 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to provide thesilyl ether 5j as a mixture of diastereomers (0.15 g, crude) which wastaken to the next step without purification.

TLC: 50% EtOAc/Hexane R_(f): (0.7 & 0.8)

5j to Examples 5 and 6

The silyl ether 10 (0.15 g, 0.38 mmol) was taken in THF (10 mL), cooledto 0° C., and a solution of KOH (60 mg, 1.1 mmol) in H₂O (5 mL) wasadded and stirred for 2 h. After completion of the reaction (by TLC),the reaction mixture was diluted with H₂O (10 mL) and extracted withEtOAc (3×15 mL). The combined organic extracts were dried over Na₂SO₄and concentrated under reduced pressure to give the crude compound whichwas purified by column chromatography to afford Example 5 (0.020 g) andExample 6 (0.011 g) both as white solids.

TLC: 50% EtOAc/Hexane R_(f): (0.3 (Example 5) & 0.6 (Example 6)).

Example 5

¹H NMR (500 MHz, CDCl₃, δ in ppm) δ: 8.67 (d, J=9.0 Hz, 1H), 8.53 (d,J=1.5 Hz, 1H), 7.88 (dd, J=9.0 Hz, 2.0 Hz, 1H), 6.66 (d, J=6.5 Hz, 1H),4.92 (m, 1H), 4.27-4.20 (m, 1H), 2.77-2.68 (m, 1H), 2.46-2.39 (m, 2H),2.12 (t, J=11.0 Hz, 1H).

Mass (ESI): 318.0 [M⁺+1]

HPLC purity: 98.58%

Example 6

¹H NMR (500 MHz, CDCl₃, δ in ppm) δ: 8.75 (d, J=9.0 Hz, 1H), 8.53 (d,J=1.5 Hz, 1H), 7.90 (dd, J=9.0 Hz, 1.5 Hz, 1H), 6.73 (d, J=6.5 Hz, 1H),4.89-4.87 (dd, J=8.0, 3.5 Hz, 1H), 4.07-4.0 (m, 1H), 2.68-2.61 (m, 1H),2.47-2.46 (m, 1H), 2.29-2.20 (m, 2H).

Mass (ESI): 318.1 [M⁺+1]

HPLC purity: 95.39%

Examples 7 and 8

(R)-2-(4-Cyano-3-(trifluoromethyl)phenyl amino)-3-hydroxypropanoic acid

To a solution of D-Serine (1) (3.65 gm, 34.8 mmol) in DMSO (30 mL),K₂CO₃ (4.36 gm, 31.6 mmol) followed by4-Fluoro-2-(trifluoromethyl)benzonitrile (7a) (3.0 gm, 15.8 mmol) wasadded and the reaction was heated to 80° C. for 4 h. After completion ofreaction (by TLC), the reaction mixture was diluted with water (100 mL)and extracted with EtOAc (150 mL). The aqueous layer was acidified withcitric acid and extracted with EtOAc (2×100 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressureto afford the crude compound which was triturated with Hexane/EtOAc toafford the acid 7b (2.1 gm, 48%) as a crystalline solid.

TLC: 30% MeOH/DCM (R_(f): 0.3)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.72 (d, J=9.0 Hz, 1H), 7.32 (d,J=8.0 Hz, 1H), 7.20 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 4.28-4.25 (m, 1H),3.81-3.74 (m, 2H).

7b to 7c(R)-Methyl-2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxypropanoate

(R)-2-(4-cyano-3-(trifluoromethyl)phenyl amino)-3-hydroxypropanoic acid(7b) (2.1 gm, 7.66 mmol) was dissolved in THF (20 mL), cooled to 0° C.,and diazomethane [prepared from N-Nitrosomethyl urea (2.32 gm, 22.9mmol) and 40% KOH solution (100 mL) in ether (60 mL)] was added to thereaction mixture and stirred for 1 h. After completion of reaction (byTLC), the reaction mixture was poured into water (80 mL) and extractedwith EtOAc (2×100 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated under reduced pressure to give the crudecompound which was purified by column chromatography to afford the ester7c (2.0 gm, 90%).

TLC: 50% EtOAc/Hexane (R_(f): 0.7)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.74 (d, J=8.5 Hz, 1H), 7.41 (d,J=8.5 Hz, 1H), 7.23 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 5.19 (t, J=5.0 Hz,1H), 4.43-4.40 (m, 1H), 3.85-3.80 (m, 1H), 3.77-3.73 (m, 1H), 3.67 (s,3H).

7c to 7d(R)-Methyl-3-(4-cyano-3-(trifluoromethyl)phenyl)-2-oxooxazolidine-4-carboxylate

To a stirred solution of(R)-Methyl-2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxypropanoate(7c) (1.0 g, 3.47 mmol) in dry CH₂Cl₂ (20 mL), cooled to −78° C., DIPEA(1.71 mL, 10.4 mmol) was added followed by Triphosgene (1.54 gm, 5.2mmol) in dissolved in CH₂Cl₂ (10 mL) under nitrogen atmosphere. Theresulting reaction mixture was slowly warmed to room temperature andstirred for 16 h. After completion of reaction (by TLC), the reactionmixture was poured into ice-cold water (60 mL) and extracted with CH₂Cl₂(2×100 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to give the crude compound which waspurified by column chromatography to afford the oxazolidinone 7d (0.091g, 84%) as syrup.

TLC: 10% MeOH/DCM (R_(f): 0.6)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.31 (d, J=1.5 Hz, 1H), 8.20 (d,J=8.0 Hz, 1H), 7.85 (dd, J=9.0, 2.0 Hz, 1H), 5.60 (dd, J=9.0, 2.5 Hz,1H), 4.75-4.66 (m, 2H), 3.73 (s, 3H).

7d to 7e(R)-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile

To a stirred solution of(R)-Methyl-3-(4-cyano-3-(trifluoromethyl)phenyl)-2-oxooxazolidine-4-carboxylate(7d) (1.3 gm, 4.14 mmol) in EtOH (50 mL), NaBH₄ (172 mg, 4.55 mmol) wasadded at 0° C. under nitrogen atmosphere. The resulting reaction mixturewas warmed to room temperature and stirred for 1 h. After completion ofreaction (by TLC), the volatiles were evaporated under reduced pressureand the residue was diluted with saturated NH₄Cl solution (100 mL) andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to give thecrude compound, The crude material was purified by column chromatographyto afford the alcohol 7e (0.65 g, 55%) as a white solid.

TLC: 50% EtOAc/Hexane (R_(f): 0.2)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.38 (d, J=1.5 Hz, 1H), 8.18 (d,J=9.0 Hz, 1H), 7.97 (dd, J=9.0, 2.0 Hz, 1H), 5.14 (t, J=5.5 Hz, 1H),4.87-4.84 (m, 1H), 4.53 (t, J=9.0 Hz, 1H), 4.38-4.35 (m, 1H), 3.67-3.63(m, 1H), 3.51-3.47 (m, 1H).

7e to Examples 7 and 8

-   4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile    7 &-   4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile    8

7e to 7f

To a solution of(S)-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile(7e) (0.4 g, 1.4 mmol) in CH₃CN (30 mL) Dess-Martin periodinane (1.19 g,2.8 mmol) was added at 0° C. under nitrogen atmosphere. The resultingreaction mixture was stirred for 10 h at 0° C. After completion ofreaction (by TLC), saturated NaHCO₃ solution (40 mL) was added to thereaction mixture and extracted with EtOAc (2×50 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford the aldehyde 7f (0.3 g, crude). The crudematerial was taken for the next step without any purification.

TLC: 10% MeOH/DCM (R_(f): 0.6)

7f to 7g

The crude aldehyde 7f (0.3 gm, 1.05 mmol) was dissolved in THF (10 mL),CsF (0.16 g, 1.05 mmol) was added followed by CF₃TMS (1.5 g, 10.5 mmol)at 0° C. under nitrogen atmosphere. The resulting reaction mixture wasstirred for 3 h at 0° C. After completion of reaction (by TLC), thereaction mixture was quenched with 0.1N NH₄Cl solution (30 mL) andextracted with EtOAc (2×80 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated under reduced pressure to afford the silylether 7g as a mixture of diastereomers (0.3 g, crude). The crude residuewas taken for the next step without further purification.

TLC: 50% EtOAc/Hexane (R_(f): 0.6).

7g to Examples 7 and 8

To a stirred solution of the crude silyl ether 7g (0.3 gm, 0.7 mmol) inTHF (10 mL), KOH (118 mg, 2.11 mmol) dissolved in water (5 mL) was addedat 0° C. and stirred for 30 min. The reaction mixture was diluted withwater (30 mL) and extracted with EtOAc (2×60 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressureto give the crude residue. The crude product was purified by columnchromatography to afford 7 (18.7 mg) and 8 (10.0 mg) both as whitesolids.

TLC: 50% EtOAc/Hexane (R_(f): 0.3 (7) & 0.7 (8))

Example 7

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.20 (d, J=8.5 Hz, 2H), 8.02 (t,J=8.5 Hz, 1H), 6.98 (d, J=7.0 Hz, 1H), 5.24 (t, J=5.5 Hz, 1H), 4.59 (t,J=8.5 Hz, 1H), 4.46-4.42 (m, 2H).

Mass (ESI) 353.2 [M⁻−1]

HPLC purity: 97.56%

Example 8

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.25 (d, J=6.0 Hz, 2H), 7.90 (d,J=9.0 Hz, 1H), 7.08 (d, J=6.5 Hz, 1H), 5.26 (t, J=6.0 Hz, 1H), 4.56 (d,J=6.5 Hz, 2H), 4.30 (t, J=7.5 Hz, 1H).

Mass (ESI): 353.6[M⁻−1]

HPLC purity: 98.06%

Examples 9 and 10

9a to 9b (R)-2-(3-chloro-4-cyanophenylamino)-3-hydroxypropanoic acid

To a stirred solution of D-Serine (2.98 gm, 28.4 mmol) in DMSO (30 mL),K₂CO₃ (3.5 gm, 25.3 mmol) followed by 2-chloro-4-fluorobenzonitrile (9a)(2.0 gm, 12.8 mmol) was added at room temperature under nitrogenatmosphere. The resulting reaction mixture was heated to 80° C. andstirred for 12 h. After completion of reaction (by TLC), the reactionmixture was diluted with water (50 mL) and extracted with EtOAc (20 mL).The aqueous layer was acidified with citric acid and extracted withEtOAc (3×30 mL). The combined organic extracts were washed with water(2×30 mL) dried over Na₂SO₄ and concentrated under reduced pressure toafford the acid 9b (1.7 gm, crude) as a white solid which was taken forthe next step without purification.

TLC: 10% MeOH/DCM (R_(f): 0.4)

¹H NMR (200 MHz, DMSO-d₆, δ in ppm): 7.54 (d, J=8.4 Hz, 1H), 7.09 (d,J=8.4 Hz, 1H), 6.86 (d, J=1.8 Hz, 1H), 6.69 (dd, J=8.8, 2.2 Hz, 1H),4.21-4.12 (m, 1H), 3.74 (dd, J=4.6, 2.6 Hz, 2H).

9b to 9c (R)-methyl 2-(3-chloro-4-cyanophenylamino)-3-hydroxypropanoate

(R)-2-(3-chloro-4-cyanophenylamino)-3-hydroxypropanoic acid (9b) (3.1gm, 12.9 mmol) was dissolved in THF (30 mL) and Diazomethane [preparedby N-Nitrosomethyl urea (6.5 gm, 64.3 mmol) and 40% KOH solution (40 mL)in ether (30 mL)] was added at 0° C. under nitrogen atmosphere. Theresulting reaction mixture was stirred for 3 h at 0° C. After completionof the reaction (by TLC), the reaction mixture was diluted with water(30 mL) and extracted with EtOAc (2×50 mL). The combined organicextracts were washed with water (2×25 mL), dried over Na₂SO₄ andconcentrated under reduced pressure to give the crude residue which waspurified by column chromatography to afford the ester 9c (3.0 gm, 93%)as a white solid.

TLC: 50% EtOAc/Hexane (R_(f): 0.6)

¹H NMR (200 MHz, DMSO-d₆, δ in ppm): 7.55 (d, J=8.8 Hz, 1H), 7.18 (d,J=8.6 Hz, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.70 (dd, J=8.6, 2.0 Hz, 1H),5.18 (t, J=5.4 Hz, 1H), 4.38-4.23 (m, 1H), 3.84-3.72 (m, 2H), 3.66 (s,3H).

Mass (ESI): 255 [M⁺+1]

9c to 9d (R)-methyl3-(3-chloro-4-cyanophenyl)-2-oxooxazolidine-4-carboxylate

To a stirred solution of (R)-methyl2-(3-chloro-4-cyanophenylamino)-3-hydroxypropanoate (9c) (1.0 gm, 4.44mmol) in dry CH₂Cl₂ (25 mL), cooled to −78° C., DIPEA (2.1 mL, 13.2mmol) followed by Triphosgene (1.9 gm, 6.4 mmol) in CH₂Cl₂ (10 mL) wasadded under nitrogen atmosphere. The resulting reaction mixture wasslowly warmed to room temperature and stirred for 12 h. After completionof reaction (by TLC), the reaction mixture was diluted with water (20mL) and extracted with CH₂Cl₂ (20 mL). The organic extract was washedwith saturated brine solution (2×15 mL), separated, dried over Na₂SO₄and concentrated under reduced pressure to provide the crude compound.The crude material was purified by column chromatography to afford theoxazolidinone 9d (0.95 gm, 79%) as a white solid.

TLC: 50% EtOAc/Hexane (R_(f): 0.7)

¹H NMR (200 MHz, DMSO-d₆, δ in ppm): 8.02-7.98 (m, 2H), 7.62 (dd, J=8.8,2.2 Hz, 1H), 5.52 (dd, J=8.8, 3.4 Hz, 1H), 4.75-4.56 (m, 2H), 3.73 (s,3H).

9d to 9e(S)-2-chloro-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)benzonitrile

To a stirred solution of(R)-Methyl-3-(3-chloro-4-cyanophenyl)-2-oxooxazolidine-4-carboxylate(9d) (0.6 gm, 2.14 mmol) in EtOH (15 mL), cooled to 0° C., NaBH₄ (84 mg,2.22 mmol) was added under nitrogen atmosphere. The resulting reactionmixture was brought to room temperature and stirred for additional 4 h.After completion of reaction (by TLC), the volatiles were evaporatedunder reduced pressure and the residue was diluted with aqueous NH₄Cl(10 mL) and extracted with EtOAc (2×20 mL). The combined organicextracts were washed with water (2×20 mL), separated, dried over Na₂SO₄and concentrated under reduced pressure to give the crude compound. Thecrude residue was triturated with hexane to provide the alcohol 9e (0.2gm, 37%) as a white solid.

TLC: 40% EtOAc/Hexane (R_(f): 0.3)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.05 (s, 1H), 7.98 (d, J=8.5 Hz,1H), 7.75 (d, J=8.5 Hz, 1H), 5.13 (t, J=5.5 Hz, 1H), 4.78-4.76 (m, 1H),4.50 (t, J=8.5 Hz, 1H), 4.35 (dd, J=8.5, 3.0 Hz, 1H), 3.65-3.61 (m, 1H),3.48-3.45 (m, 1H).

9e to Examples 9 and 102-chloro-4-((S)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile9 &2-chloro-4-((S)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)

9e to 9f

To a stirred solution of(S)-2-Chloro-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)benzonitrile (9e)(0.5 gm, 1.78 mmol) in CH₃CN (20 mL) Dess-Martin periodinane (1.1 gm,2.6 mmol), was added at 0° C. under nitrogen atmosphere. The resultingreaction mixture was brought to room temperature and stirred for 2 h.After completion of reaction (by TLC), saturated NaHCO₃ solution (40 mL)was added to the reaction mixture and extracted with EtOAc (2×20 mL).The combined organic extracts were washed with water (2×20 mL),separated, dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford the aldehyde 9f (0.35 gm, crude). The crude materialwas taken for the next step without any purification.

TLC: 10% MeOH/DCM (R_(f): 0.7)

9f to 9g

The crude aldehyde 9f (0.3 gm, 1.01 mmol) was dissolved in THF (10 mL),cooled to 0° C., and CsF (0.15 gm, 1.0 mmol) followed by CF₃TMS (1.4 gm,9.8 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h.After completion of reaction (by TLC), the reaction mixture was quenchedwith saturated NH₄Cl solution (20 mL) and extracted with EtOAc (2×20mL). The combined organic extracts were washed with water (2×20 mL). Theorganic layer was separated, dried over Na₂SO₄ and concentrated underreduced pressure to afford the silyl ether 9g as a mixture ofdiastereomers (0.2 gm, crude) which was used for the next step withoutpurification.

TLC: 50% EtOAc/Hexane (R_(f): 0.8 & 0.9)

9g to Example 9 and 10

To a stirred solution of the silyl ether 9g (0.2 gm, 0.5 mmol) in THF (5mL), KOH (85 mg, 1.5 mmol) taken in water (5 mL) was added at 0° C. Theresulting reaction mixture was stirred at 0° C. for 1 h. Aftercompletion of reaction (by TLC), the reaction mixture was diluted withwater (5 mL) and extracted with EtOAc (2×10 mL). The combined organicextracts were washed with water (2×10 mL) and the organic layer wasseparated, dried over Na₂SO₄ and concentrated under reduced pressure toprovide the crude mixture. The crude residue was purified by columnchromatography during which 9 and 10 were separated but were stillcontaminated with impurities. Impure 9 was purified by preparative HPLCto afford 0.016 g of pure compound as a white solid. On the other hand,impure 10 was further purified by column chromatography and trituratedwith n-pentane to provide 0.020 g of pure compound as a white solid.

TLC: 60% EtOAc/Hexane (R_(f): 0.3 9 & 0.5 10)

Example 9

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.00 (d, J=9.0 Hz, 1H), 7.96 (s,1H), 7.72 (d, J=8.5 Hz, 1H), 6.96 (d, J=7.0 Hz, 1H), 5.15 (br s, 1H),4.56 (t, J=8.5 Hz, 1H), 4.46-4.40 (m, 2H).

Mass (ESI) 320.1 [M⁺]

HPLC purity: 95.7%

Example 10

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.06 (d, J=9.0 Hz, 1H), 7.98 (s,1H), 7.61 (dd, J=8.5, 2.0 Hz, 1H), 7.10 (d, J=7.0 Hz, 1H), 5.18 (t,J=6.0 Hz, 1H), 4.56-4.52 (m, 2H), 4.25 (t, J=7.5 Hz, 1H).

Mass (ESI): 319.8 [M⁻−1]

HPLC purity: 98.0%

Examples 11 and 12

11a to 11b(R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxypropanoic acid

To a stirred solution of 2-chloro-4-fluoro-3-methylbenzonitrile (11a)(1.0 gm, 5.8 mmol) in DMSO (10 mL), D-Serine (1.4 gm, 13.3 mmol) wasadded followed by K₂CO₃ (1.7 gm, 12.3 mmol) at room temperature. Theresulting reaction mixture was heated to 90° C. for 12 h. Aftercompletion of reaction (by TLC), the reaction mixture was poured intoice-cold water (300 mL) and extracted with EtOAc (100 mL). The aqueouslayer was acidified with citric acid (pH˜3) and extracted with EtOAc(2×100 mL). The combined organic extracts were dried over Na₂SO₄, andconcentrated under reduced pressure to afford the acid 11b (0.3 gm,crude) as off-white solid. The crude material was taken for the nextstep without purification.

TLC: 10% MeOH/DCM (R_(f): 0.2)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.2-10.2 (br s, 1H), 7.54 (d, J=8.5Hz, 1H), 6.57 (d, J=9.0 Hz, 1H), 5.79 (d, J=7.5 Hz, 1H), 4.20 (t, J=3.0Hz, 1H), 3.86-3.79 (m, 2H), 3.22 (br s, 1H), 2.25 (s, 3H).

11b to 11c (R)-Methyl2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxypropanoate

To a solution of (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxypropanoic acid (11b) (0.3 g, 1.1 mmol) in THF (20 mL), diazomethane[prepared by N-Nitrosomethyl urea (0.35 g, 3.4 mmol) and 40% KOHsolution (20 mL) in ether (30 mL)] was added at 0° C. and the resultingreaction mixture was stirred at 0° C. for 3 h. After completion ofreaction (by TLC), the reaction mixture was diluted with water (30 mL)and extracted with EtOAc (2×50 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to give thecrude compound which was purified by column chromatography to afford theester 11c (0.25 g, 80%) as a white solid.

TLC: 50% EtOAc/Hexane (R_(f): 0.6)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.54 (d, J=9.0 Hz, 1H), 6.57 (d,J=9.0 Hz, 1H), 5.83 (d, J=8.5 Hz, 1H), 5.24 (t, J=6.0 Hz, 1H), 4.39-4.37(m, 1H), 3.88-3.84 (m, 2H), 3.66 (s, 3H), 2.26 (s, 3H).

11c to 11d (R)-Methyl3-(3-chloro-4-cyano-2-methylphenyl)-2-oxooxazolidine-4-carboxylate

To a solution of (R)-Methyl 2-(3-chloro-4-cyano-2-methyl phenylamino)-3-hydroxypropanoate (11c) (250 mg, 0.92 mmol) in dry CH₂Cl₂ (10mL), cooled to −78° C., DIPEA (0.5 mL, 3.0 mmol) followed by Triphosgene(0.4 g, 1.3 mmol) in CH₂Cl₂ (5 mL) was added under nitrogen atmosphere.The resulting reaction mixture was slowly brought to room temperatureand stirred for 12 h. After completion of reaction (by TLC), thereaction mixture was diluted with water (30 mL) and extracted withCH₂Cl₂ (2×50 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudecompound. The crude material was purified by column chromatography toafford oxazolidinone 11d (0.150 g, 55%).

TLC: 10% MeOH/DCM (R_(f): 0.5)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.92 (d, J=8.5 Hz, 1H), 7.64 (d,J=8.5 Hz, 1H), 5.31-5.28 (m, 1H), 4.82 (t, J=9.0 Hz, 1H), 4.60-4.58 (m,1H), 3.63 (s, 3H), 2.34 (s, 3H).

11d to 11e (S)-2-chloro-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)-3-methylbenzonitrile

To a stirred solution of (R)-Methyl3-(3-chloro-4-cyano-2-methylphenyl)-2-oxo oxazolidine-4-carboxylate(11d) (0.15 g, 0.5 mmol) in EtOH (20 mL), cooled to 0° C., NaBH₄ (21 mg,0.56 mmol) was added. The resulting reaction mixture was allowed to warmup to room temperature and stirred for further 4 h. After completion ofreaction (by TLC), the volatiles were evaporated under reduced pressureand the residue was diluted with water (40 mL) and extracted with EtOAc(2×50 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudecompound which was purified by column chromatography to provide thealcohol 11e (0.085 g, 65%).

TLC: 10% MeOH/DCM (R_(f): 0.3)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.92 (d, J=8.5 Hz, 1H), 7.59 (d,J=8.5 Hz, 1H), 5.08 (t, J=5.0 Hz, 1H), 4.60 (t, J=9.0 Hz, 1H), 4.46 (bs,1H), 4.34-4.32 (m, 1H), 3.42-3.38 (m, 1H), 3.34-3.31 (m, 1H), 2.31 (s,3H).

11e to Example 11 and 122-chloro-3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile 112-chloro-3-methyl-4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile 12

11e to 11f

To a stirred solution of (S)-2-chloro-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)-3-methylbenzonitrile (11e) (0.8 g, 3.0 mmol) in CH₃CN(100 mL), cooled to 0° C., Dess-Martin periodinane (2.5 gm, 6.0 mmol)was added and the resulting reaction mixture was slowly brought to roomtemperature and stirred for additional 2 h. After completion of reaction(by TLC), saturated NaHCO₃ solution (80 mL) was added to the reactionmixture and extracted with EtOAc (2×100 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressureto afford the aldehyde 11f (0.45 g, crude) as a solid which was takenfor the next step without purification.

TLC: 10% MeOH/DCM (R_(f): 0.6)

11f to 11g

To a solution of the aldehyde 11f (0.45 gm, 1.5 mmol) in THF (10 mL),cooled to 0° C., CsF (0.22 g, 1.5 mmol) was added followed by CF₃TMS(0.22 g, 1.5 mmol) and stirred for 2 h at 0° C. After completion ofreaction (by TLC), the reaction mixture was quenched with saturatedNH₄Cl solution (40 mL) and extracted with EtOAc (2×100 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under vacuo toafford the silyl ether 11g as a mixture of diastereomers (0.5 g, crude).The crude material was carried forward without purification. TLC: 50%EtOAc/Hexane (R_(f): 0.8 & 0.9)

11g to Example 11 and 12

The crude silyl ether 1g (0.5 g, 1.2 mmol) was dissolved in THF (20 mL),cooled to 0° C., KOH (0.2 g, 3.6 mmol) taken in water (20 mL) was added.The resulting reaction mixture was stirred at 0° C. for 2 h. Aftercompletion of reaction (by TLC), the reaction mixture was diluted withwater (50 mL) and extracted with EtOAc (2×100 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressureto give the crude mixture which was purified by column chromatographyfollowed by preparative HPLC to afford 11 (0.040 g) and 12 (0.130 g)both as off-white solids.

TLC: 50% EtOAc/Hexane (R_(f): 0.3 11 & 0.6 12)

Example 11

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.88 (d, J=8.0 Hz, 1H), 7.68 (d,J=8.5 Hz, 1H), 6.86 (d, J=7.0 Hz, 1H), 4.82 (br s, 1H), 4.69 (t, J=9.0Hz, 1H), 4.37-4.32 (m, 2H), 2.33 (s, 3H).

HPLC purity: 95.82%

Example 12

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.97 (d, J=8.5 Hz, 1H), 7.66 (br s,1H), 7.10 (br s, 1H), 4.85 (br s, 1H), 4.61 (t, J=8.5 Hz, 1H), 4.53 (t,J=7.0 Hz, 1H), 3.99-3.95 (m, 1H), 2.31 (s, 3H).

HPLC purity: 98

Example 13 and 14

13a to 13b 4-Fluoro-3-methyl-2-(trifluoromethyl)benzo nitrile

To a solution of 2,2,6,6-tetramethylpiperidine (1.4 mL, 8.2 mmol) in dryTHF (4 mL), cooled to −78° C., n-BuLi (2.9 mL, 2.5M solution in hexane,8.2 mmol) was added drop wise under nitrogen atmosphere. After beingstirred for 30 min at −78° C., the resulting solution was brought to−20° C. and stirred for additional 30 min.4-fluoro-2-(trifluoromethyl)benzonitrile (13a) (1.0 g, 5.2 mmol) wasdissolved in dry THF (8 mL), cooled to −78° C., and the above preparedlithiated piperidine solution was added under nitrogen atmosphere. After5 h, MeI (0.6 mL, 9.3 mmol) was added to the reaction mixturemaintaining the temperature at −78° C. The resulting reaction mixturewas slowly brought to room temperature and stirred for 16 h. Aftercompletion of reaction (by TLC), aqueous NH₄Cl (20 mL) was added to thereaction mixture and extracted with EtOAc (2×20 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure to give the crude compound. The crude material was purified bycolumn chromatography to afford the nitrile 13b (0.25 g, 25%) as ayellow oil.

TLC: 7% EtOAc/Hexane (R_(f): 0.5)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 7.69 (dd, J=8.0 Hz, 5.5 Hz, 1H), 7.34(d, J=8.5 Hz, 1H), 2.45 (s, 3H).

13b to 13c(R)-2-((4-cyano-2-methyl-3-(trifluoromethyl)phenyl)amino)-3-hydroxypropanoicacid

To a solution of D-Serine (0.85 g, 4.2 mmol) in DMSO (20 mL), at roomtemperature, K₂CO₃ (1.13 g, 8.3 mmol) was added followed by4-fluoro-3-methyl-2-(trifluoromethyl)benzo nitrile (13b) (0.88 g, 8.3mmol). The resulting reaction mixture was then heated to 80° C. for 16h, diluted with water (20 mL) and acidified to pH˜3 using citric acid.The aqueous layer was extracted with EtOAc (3×20 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure to give the crude compound which was triturated with 10%EtOAc/hexane to afford the acid 13c (0.65 g, 54%) as an off-white solid.

TLC: 30% EtOAc/Hexane (R_(f): 0.3)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.30-9.50 (br s, 1H), 7.66 (d,J=9.0 Hz, 1H), 6.87 (d, J=9.0 Hz, 1H), 5.92 (d, J=7.5 Hz, 1H), 4.28-4.26(m, 1H), 3.89-3.84 (m, 2H), 3.30-3.50 (br s, 1H), 2.26 (s, 3H).

Mass (ESI): 286.9 [M⁺−1]

13c to 13d (R)-methyl2-((4-cyano-2-methyl-3-(trifluoromethyl)phenyl)amino)-3-hydroxypropanoate

To a solution of(R)-2-((4-cyano-2-methyl-3-(trifluoromethyl)phenyl)amino)-3-hydroxypropanoicacid (13c) (0.8 g, 2.7 mmol) in THF (20 mL), cooled to 0° C.,diazomethane [prepared by N-Nitrosomethyl urea (0.84 g, 8.3 mmol) and40% KOH solution (20 mL) in ether (20 mL)] was added under nitrogenatmosphere and stirred for 15 min. After completion of the reaction (byTLC), the reaction mixture was diluted with water (20 mL) and extractedwith EtOAc (3×20 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated under reduced pressure to afford the ester 13d(0.7 g, crude) as a white solid which was carried forward to the nextstep without purification.

TLC: 50% EtOAc/Hexane (R_(f): 0.7)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 7.53 (d, J=8.5 Hz, 1H), 6.71 (d,J=8.5 Hz, 1H), 5.30 (d, J=7.0 Hz, 1H), 4.29-4.26 (m, 1H), 4.13-4.09 (m,1H), 4.08-4.00 (m, 1H), 3.84 (s, 3H), 2.33 (s, 3H), 1.98 (t, J=6.0 Hz,1H).

Mass (ESI): 303.9 [M⁺+1]

13d to 13e (R)-methyl3-(4-cyano-2-methyl-3-(trifluoromethyl)phenyl)-2-oxooxazolidine-4-carboxylate

To a solution of (R)-methyl 2-((4-cyano-2-methyl-3-(trifluoromethyl)phenyl)amino)-3-hydroxypropanoate (13d) (0.7 g, 2.3 mmol) in dryCH₂Cl₂ (20 mL), cooled to −78° C., DIPEA (1.1 mL, 6.9 mmol) followed byTriphosgene (1.1 g, 3.6 mmol) dissolved in dry CH₂Cl₂ (5 mL) was addedunder nitrogen atmosphere. The resulting reaction mixture was brought toroom temperature and stirred for 16 h. After completion of reaction (byTLC), the reaction mixture was diluted with water (30 mL) and extractedwith CH₂Cl₂ (3×15 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated under reduced pressure to give the crudecompound. The crude material was purified by column chromatography toprovide the oxazolidinone 13e (0.65 g, 85%) as a white solid.

¹H NMR (500 MHz, CDCl₃, δ in ppm): 7.73 (d, J=8.5 Hz, 1H), 7.66 (d,J=7.5 Hz, 1H), 4.83-4.77 (m, 2H), 4.56 (dd, J=9.0, 4.5 Hz, 1H), 3.74 (s,3H), 2.49 (d, J=1.5 Hz, 3H).

TLC: 5% CH₃OH/CH₂Cl₂ (R_(f): 0.8)

13e to 13f(S)-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)-3-methyl-2-(trifluoromethyl)benzonitrile

To a solution of (R)-methyl3-(4-cyano-2-methyl-3-(trifluoromethyl)phenyl)-2-oxooxazolidine-4-carboxylate(13e) (0.6 g, 1.8 mmol) in EtOH (10 mL), cooled to 0° C., NaBH₄ (0.084g, 2.2 mmol) was added under nitrogen atmosphere. The resulting reactionmixture was warmed to room temperature and stirred for 3 h. Aftercompletion of reaction (by TLC), the volatiles were removed underreduced pressure and the residue was diluted with saturated NH₄Clsolution (20 mL) and extracted with EtOAc (3×15 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure to give the crude compound which was purified by columnchromatography to furnish the alcohol 13f (0.35 g, 64%) as white syrupymass.

TLC: 100% EtOAc (R_(f): 0.45)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.07 (d, J=8.0 Hz, 1H), 7.91 (d,J=8.0 Hz, 1H), 5.11 (s, 1H), 4.61 (t, J=9.0 Hz, 1H), 4.34 (t, J=8.0 Hz,1H), 3.42-3.40 (m, 2H), 2.39 (d, J=2.0 Hz, 3H).

13f to Examples 13 and 143-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile 13 &3-Methyl-4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoro methyl)benzonitrile 14

13f to 13g

To a solution of(S)-4-(4-(hydroxymethyl)-2-oxooxazolidin-3-yl)-3-methyl-2-(trifluoromethyl)benzonitrile(13f) (0.45 g, 1.5 mmol) in CH₃CN (20 mL), cooled to 0° C., Dess-Martinperiodinane (1.27 g, 3.0 mmol) was added. The reaction was stirred at 0°C. for 16 h, quenched with saturated NaHCO₃ solution (20 mL) andextracted with CH₂Cl₂ (3×15 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to provide thealdehyde 13g (0.36 g, crude). The crude material was used for the nextstep without purification.

TLC: 10% MeOH/CH₂Cl₂ (eluted twice) (R_(f): 0.65)

13g to 13h

The crude aldehyde 13g (0.36 g, 1.2 mmol) was dissolved in THF (20 mL),cooled to 0° C., and CsF (174 mg, 1.15 mmol) followed by CF₃TMS (1.8 mL,12.0 mmol) was added. The reaction mixture was stirred at 0° C. for 4 h.After the completion of reaction (by TLC), the reaction mixture wasquenched with saturated NH₄Cl solution (20 mL) and extracted with EtOAc(3×20 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to provide the silyl ether 13h as amixture of diastereomers (0.3 g, crude). The crude material was taken tothe next step without purification.

TLC: 100% EtOAc (R_(f): 0.7 & 0.8)

13h to Examples 13 and 14

The crude silyl ether 13h (0.3 g, 0.68 mmol) was taken in THF (10 mL),cooled to 0° C., and KOH (0112 g, 2.03 mmol) dissolved in water (10 mL)was added. The reaction mixture was stirred at 0° C. for 1 h, dilutedwith water (20 mL) and extracted with EtOAc (3×10 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under vacuo toprovide the crude residue which was purified by column chromatographyfollowed by preparative HPLC to furnish 13 (0.050 g) and 14 (0.018 g)both as white solids.

TLC: 60% EtOAc/Hexane (R_(f): 13 0.3 & 0.7 14)

Example 13

¹H NMR (500 MHz, CDCl₃, δ in ppm): 7.73 (d, J=8.0 Hz, 1H), 7.60 (br s,1H), 4.74 (t, J=9.5 Hz, 1H), 4.65 (m, 1H), 4.50-4.47 (t, J=9.0 Hz, 1H),4.17 (m, 1H), 2.61 (s, 1H), 2.50 (s, 3H).

HPLC purity: 98.13%

Mass (ESI): 367.7[M⁺−1]

Example 14

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.12 (d, J=8.0 Hz, 1H), 8.07 (br s,1H), 7.13 (s, 1H), 5.05 (br s, 1H), 4.62-4.53 (m, 2H), 4.02 (t, J=8.0Hz, 1H), 2.38 (s, 3H).

HPLC purity: 92.98%

Mass (ESI): 481.1 [M⁺+TFA]

Examples 15 and 16

15a to 15b (2R,3R)-Methyl2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoate

To a solution of(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy butanoic acid(can be prepared according to procedure described in WO2009/105214)(15a) (3 g, 11.16 mmol) in dry THF (20 mL), cooled to 0° C.,diazomethane [prepared from N-Nitrosomethyl urea (2 g, 19.8 mmol) and40% solution of KOH (90 mL) in ether (100 mL)] was added. The resultingreaction mixture was stirred for 30 min at 0° C. After completion ofreaction (by TLC), the volatiles were evaporated under reduced pressureto give the crude compound. The crude material was purified by columnchromatography to afford the ester 15b (2.2 g, 69%) as a white solid.

TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.8)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.56 (d, J=8.5 Hz, 1H), 6.57 (d,J=9.0 Hz, 1H), 5.90 (d, J=8.0 Hz, 1H), 5.27 (d, J=5.5 Hz, 1H), 4.15-4.07(m, 2H), 3.65 (s, 3H), 2.26 (s, 3H), 1.21 (d, J=6.0 Hz, 3H).

15b to 15c (4R,5R)-methyl3-(3-chloro-4-cyano-2-methylphenyl)-5-methyl-2-oxooxazolidine-4-carboxylate

To a solution of (2R,3R)-Methyl2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy butanoate (15b) (1.7g, 6.0 mmol) in dry CH₂Cl₂ (30 mL), cooled to −78° C., DIPEA (3.0 mL,18.2 mmol) was added followed by Triphosgene (2.66 g, 9.0 mmol)dissolved in CH₂Cl₂ (10 mL). The resulting reaction mixture was allowedto warm to room temperature and stirred for 16 h. After completion ofreaction (by TLC), the reaction mixture was diluted with ice-cold water(40 mL) and extracted with CH₂Cl₂ (2×50 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the crude compound. The crude material was purified bysilica gel column chromatography to afford the oxazolidinone 15c (1.5 g,81%) as a white solid.

TLC: 5% MeOH/CH₂Cl₂ (R_(f): 0.8)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.90 (d, J=8.5 Hz, 1H), 7.60 (d,J=9.0 Hz, 1H), 5.35 (d, J=8.0 Hz, 1H), 5.23-5.20 (m, 1H), 3.70 (s, 3H),2.38 (s, 3H), 1.26 (d, J=5.5 Hz, 3H).

15c to 15d2-chloro-4-((4S,5R)-4-(hydroxymethyl)-5-methyl-2-oxooxazolidin-3-yl)-3-methylbenzonitrile

To a stirred solution of (4R,5R)-methyl 3-(3-chloro-4-cyano-2-methylphenyl)-5-methyl-2-oxooxazolidine-4-carboxylate (15c) (1.5 g, 4.8 mmol)in EtOH (100 mL), cooled to 0° C., NaBH₄ (0.2 g, 5.3 mmol) was added andthe resulting reaction mixture was stirred for further 2 h. Aftercompletion of reaction (by TLC), the volatiles were removed underreduced pressure and the residue was diluted with cold water (30 mL) andextracted with EtOAc (2×50 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated under reduced pressure to give the crudecompound which was purified by column chromatography to provide thealcohol 15d (1.1 g, 80%) as syrup.

TLC: 50% EtOAc/Hexane (R_(f): 0.4)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.92 (d, J=8.5 Hz, 1H), 7.59 (d,J=8.0 Hz, 1H), 5.05-5.01 (m, 1H), 4.70-4.65 (m, 1H), 4.05 (br s, 1H),3.47-3.39 (m, 1H), 3.35-3.31 (m, 1H), 2.33 (s, 3H), 1.49 (d, J=6.5 Hz,3H).

Mass (ESI): 279.4 [M⁺−1]

15d to Examples 15 and 162-chloro-3-methyl-4-((4S,5R)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile 15 &2-chloro-3-methyl-4-((4S,5R)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile16

15d to 15e

To a solution of2-chloro-4-((4S,5R)-4-(hydroxymethyl)-5-methyl-2-oxooxazolidin-3-yl)-3-methylbenzonitrile(15d) (0.5 g, 1.8 mmol) in CH₃CN (30 mL), cooled to 0° C., Dess-Martinperiodinane (1.45 g, 3.42 mmol) was added. The resulting reactionmixture was slowly brought to room temperature and stirred for 30 min.After completion of reaction (by TLC), saturated NaHCO₃ solution (30 mL)was added to the reaction mixture and extracted with EtOAc (2×50 mL).The combined organic extracts were dried over Na₂SO₄ and concentratedunder reduced pressure to afford the aldehyde 15e (0.45 g, crude) as asyrup which was taken for the next step without further purification.

TLC: 10% MeOH/DCM (R_(f): 0.7).

15e to 15f

The crude aldehyde 15e (0.45 g, 1.6 mmol) was dissolved in THF (50 mL),cooled to 0° C., and CsF (245 mg, 1.6 mmol) was added followed by CF₃TMS(2.3 g, 16.2 mmol). The resulting reaction mixture was stirred for 2 hat 0° C. After completion of reaction (by TLC), the reaction mixture wasquenched with saturated NH₄Cl solution (50 mL) and extracted with EtOAc(2×100 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to afford the silyl ether 15f as amixture of diastereomers (0.6 g, crude) which was carried forwardwithout purification.

TLC: 50% EtOAc/Hexane (R_(f): 0.6 & 0.8)

15f to Examples 15 and 16

To a solution of silyl ether 15f (0.6 gm, 1.4 mmol) in THF (20 mL),cooled to 0° C., KOH (0.24 gm, 4.3 mmol) in water (20 mL) was added. Theresulting reaction mixture was stirred at 0° C. for 1 h, diluted withwater (40 mL) and extracted with EtOAc (2×80 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressureto give the crude mixture which was purified by column chromatographyfollowed by preparative HPLC to afford 15 (35 mg) and 16 (18 mg) both aswhite solids.

TLC: 50% EtOAc/Hexane (R_(f): 0.3 15 & 0.6 16)

Example 15

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.89 (d, J=8.5 Hz, 1H), 7.74 (br s,1H), 6.93 (d, J=6.5 Hz, 1H), 4.66 (t, J=5.5 Hz, 1H), 4.40 (d, J=8.0 Hz,2H), 2.33 (s, 3H), 1.53 (d, J=6.0 Hz, 3H)

Mass (ESI): 347.1 [M⁺−1]

HPLC purity; 99.75%

Example 16

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.97 (d, J=8.5 Hz, 1H), 7.75 (br s,1H), 7.11 (br s, 1H), 4.90 (t, J=6.0 Hz, 1H), 4.55 (bs, 1H), 3.96 (t,J=6.0 Hz, 1H), 2.31 (s, 3H), 1.50 (d, J=6.0 Hz, 3H).

Mass (ESI): 347.0 [M⁺−1]

HPLC purity: 98.68%

Examples 17 and 18

To a stirred solution of D-Threonine (4.63 g, 38.8 mmol) in DMSO (50mL), cooled to 0° C. K₂CO₃ (4.7 g, 34.8 mmol) was added. After beingstirred for 15 min, 2-chloro-4-fluoro-3-methylbenzonitrile (3.0 g, 17.7mmol) was added to the reaction mixture. The resulting reaction mixturewas heated to 80° C. for 36 h. After completion of reaction (by TLC),the reaction mixture was brought to room temperature, diluted with water(50 mL) and extracted with EtOAc (3×30 mL). The aqueous layer wasacidified by citric acid (pH 2-3) and extracted with EtOAc (3×50 mL).The combined organic extracts were washed with ice-cold water (5×30 mL),dried over Na₂SO₄ and concentrated under reduced pressure to give thecrude product. The crude material was triturated with 10% EtOAc/Hexaneto afford the acid 17a (2.0 g, 42%) as an off-white solid.

TLC: 30% MeOH/DCM (R_(f): 0.2)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.54 (d, J=8.5 Hz, 1H), 6.58 (d,J=9.0 Hz, 1H), 5.46 (d, J=9.0 Hz, 1H), 4.25-4.23 (dd, J=6.5, 3.5 Hz,1H), 4.13-4.11 (dd, J=8.5, 3.0 Hz, 1H), 2.26 (s, 3H), 1.19 (d, J=6.5 Hz,3H).

17a to 17b(2R,3S)-methyl-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoate

To a solution of(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid(17a) (2.0 g, 7.9 mmol) in THF (20 mL), cooled to 0° C., diazomethane[prepared by N-Nitrosomethyl urea (2.2 g) and 40% KOH solution (90 mL)in ether (40 mL)] was added and stirred for 15 min. After completion ofreaction (by TLC), the reaction mixture was diluted with water (50 mL).The organic layer was separated, dried over Na₂SO₄ and concentratedunder reduced pressure to give crude compound which was triturated withhexane to afford the ester 17b (1.8 g, 86%) as a white solid.

TLC: 50% EtOAc/Hexane (R_(f): 0.6)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 7.38 (d, J=8.5 Hz, 1H), 6.45 (d,J=8.5 Hz, 1H), 5.06 (d, J=8.0 Hz, 1H), 4.36 (br s, 1H), 4.04 (dd, J=8.5,2.5 Hz, 1H), 3.79 (s, 3H), 2.32 (s, 3H), 2.20 (d, J=3.5 Hz, 1H), 1.33(d, J=6.5 Hz, 3H).

Mass (ESI): 283 [M+1]

17b to 17c (4R,5S)-Methyl3-(3-chloro-4-cyano-2-methylphenyl)-5-methyl-2-oxooxazolidine-4-carboxylate

To a solution of (2R,3S)-Methyl2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoate (17b) (1.8g, 6.3 mmol) in dry CH₂Cl₂ (20 mL), cooled to −78° C., DIPEA (3 mL) wasadded followed by Triphosgene (2.8 g, 9.5 mmol) taken in CH₂Cl₂ (10 mL).The reaction mixture was slowly brought to room temperature and stirredfor 16 h. After completion of reaction (by TLC), the reaction mixturewas diluted with water (50 mL) and extracted with CH₂Cl₂ (3×50 mL). Thecombined organic extracts were washed with water (3×50 mL), dried overNa₂SO₄, and concentrated under reduced pressure to give the crudecompound. The crude material was purified by column chromatography toprovide the oxazolidinone 17c (1.2 g, 61%) as an off white solid.

TLC: 40% EtOAc/Hexane (R_(f): 0.6)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 7.56 (d, J=8.0 Hz, 1H), 7.30 (d,J=8.0 Hz, 1H), 4.77 (t, J=6.0 Hz, 1H), 4.43 (d, J=5.5 Hz, 1H), 3.73 (s,3H), 2.43 (s, 3H), 1.70 (d, J=6.5 Hz, 3H).

17c to 17d2-chloro-4-((4S,5S)-4-(hydroxymethyl)-5-methyl-2-oxooxazolidin-3-yl)-3-methylbenzonitrile

The oxazolidinone 17c (1.2 gm, 4.0 mmol) was taken in EtOH (20 mL),cooled to 0° C., and NaBH₄ (0.176 g, 4.6 mmol) was added and stirred at0° C. for 4 h. After completion of reaction (by TLC), the volatiles wereevaporated under reduced pressure and the residue was diluted withaqueous NH₄Cl (30 mL) and extracted with EtOAc (3×50 mL). The combinedorganic extracts were washed with aqueous NH₄Cl (2×50 mL). The organiclayer was separated, dried over Na₂SO₄, and concentrated under reducedpressure to give the crude compound which was purified by columnchromatography to furnish the alcohol 17d (1.0 g, 91%) as an off-whitesolid.

TLC: 60% EtOAc/Hexane (R_(f): 0.3)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.92 (d, J=8.5 Hz, 1H), 7.59 (d,J=8.5 Hz, 1H), 5.06 (t, J=5.0 Hz, 1H), 4.70-4.65 (m, 1H), 4.05 (br s,1H), 3.44-3.40 (m, 1H), 3.35-3.31 (m, 1H), 2.30 (s, 3H), 1.49 (d, J=6.5Hz, 3H).

17d to Examples 17 and 182-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile17 &2-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile18

17d to 17e

To a stirred solution of2-chloro-4-((4S,5S)-4-(hydroxymethyl)-5-methyl-2-oxooxazolidin-3-yl)-3-methylbenzonitrile(17d) (0.6 g, 2.14 mmol) in CH₃CN (20 mL), cooled to 0° C., Dess-Martinperiodinane (1.8 g, 4.2 mmol) was added portion wise at under nitrogenatmosphere. The reaction mixture was stirred at 0° C. for further 3 h.After completion of reaction (by TLC), the reaction mixture was dilutedwith aqueous NaHCO₃ solution (20 mL) and extracted with CH₂Cl₂ (2×50mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to afford the aldehyde 17e (0.5 g,crude) as an off-white solid which was taken for the next step withoutpurification.

TLC: 10% MeOH/DCM (R_(f): 0.5)

17e to 17f

To a solution of the crude aldehyde 17e (0.5 g, 1.79 mmol) in dry THF(30 mL), cooled to 0° C., CsF (0.271 g, 1.7 mmol) was added followed byCF₃TMS (3.6 mL, 17.6 mmol) under nitrogen atmosphere. The reaction wascontinued at 0° C. for 16 h. After completion of reaction (by TLC), thereaction mixture was quenched with aqueous NH₄Cl (30 mL) and extractedwith EtOAc (3×30 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated under reduced pressure to afford the silyl ether17f as a mixture of diastereomers (0.4 g, crude). The crude material wasused for the next step without purification.

TLC: 50% EtOAc/Hexane (R_(f): 0.3&0.6)

17f to Examples 17 and 18

The crude silyl ether 17f (0.4 gm, 0.95 mmol) was dissolved in THF (20mL), cooled to 0° C., and KOH (0.156 g, 0.28 mmol) taken in water (20mL) was added. The reaction was stirred at 0° C. for 2 h. Aftercompletion of reaction (by TLC), the reaction mixture was diluted withwater (20 mL) and extracted with EtOAc (3×30 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated under vacuo to providethe crude mixture which was purified by column chromatography to afford17 (0.032 g) and 18 (0.016 g) both as white solids.

TLC: 50% EtOAc/Hexane (R_(f): 0.3 17 & 0.4 18)

Example 17

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.89 (d, J=8.5 Hz, 1H), 7.73 (br s,1H), 6.93 (d, J=6.0 Hz, 1H), 4.67 (d, J=5.0 Hz, 1H), 4.39 (d, J=7.0 Hz,2H), 2.33 (s, 3H), 1.53 (d, J=6.5 Hz, 3H).

Mass: 347.3 [M⁺−1] HPLC purity: 96.3%

Example 18

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.97 (d, J=8.0 Hz, 1H), 7.78 (br s,1H), 7.11 (br s, 1H), 4.89 (t, J=5.5 Hz, 1H), 4.44-4.42 (br s, 1H), 3.95(m, 1H), 2.30 (s, 3H), 1.49 (d, J=6.5 Hz, 3H).

Mass: 347.3 [M⁺−1] HPLC purity: 99.4%

Examples 19 and 20

19a to 19b (2R,3S)-2-(4-Cyano-3-(trifluoro methyl)phenylamino)-3-hydroxybutanoic acid

To a solution of D-Threonine (4.14 g, 34.8 mmol) in DMSO (30 mL), K₂CO₃(4.36 g, 31.6 mmol) followed by 4-Fluoro-2-(trifluoromethyl)benzonitrile(19a) (3.0 g, 15.8 mmol) was added at room temperature. The reaction washeated to 80° C. for 16 h. After completion of reaction (by TLC), thereaction mixture was diluted with water (100 mL) and extracted withEtOAc (3×50 mL). The aqueous layer was acidified with citric acid andextracted with EtOAc (2×100 mL). The combined organic extracts weredried over Na₂SO₄ and concentrated under reduced pressure to afford theacid 19b (2.02 g, crude) as syrup which was taken for the next stepwithout purification.

TLC: 30% MeOH/DCM (R_(f): 0.4)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.71 (d, J=9.0 Hz, 1H), 7.27 (br s,1H), 7.15 (d, J=8.5 Hz, 1H), 6.93 (br s, 1H), 4.24-4.21 (m, 1H),4.15-4.13 (m, 1H), 3.32 (br s, 1H), 1.19-1.16 (m, 3H).

19b to 19c (2R,3S)-Methyl2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxy butanoate

(2R,3S)-2-(4-Cyano-3-(trifluoro methyl)phenyl amino)-3-hydroxybutanoicacid (19b) (2.0 g, 6.94 mmol) was dissolved in THF (20 mL), cooled to 0°C., and diazomethane [prepared by N-Nitrosomethyl urea (2.1 g, 20.8mmol) and 40% KOH solution (100 mL) in ether (40 mL)] was added. Theresulting reaction mixture was slowly warmed to room temperature andstirred for 30 min. After completion of reaction (by TLC), the reactionmixture was poured into water (80 mL) and extracted with EtOAc (2×100mL). The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the crude compound. Thecrude material was purified by column chromatography to afford the ester19c (1.8 g, 86%) as a syrup.

TLC: 50% EtOAc/Hexane (R_(f): 0.5)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.20 (d, J=8.5 Hz, 1H), 7.30 (br s,1H), 7.23 (d, J=8.5 Hz, 1H), 6.93 (br s, 1H), 5.16 (d, J=5.5 Hz, 1H),4.32 (dd, J=9.0, 3.0 Hz, 1H), 4.25-4.22 (m, 1H), 3.66 (s, 3H), 1.19-1.14(m, 3H).

19c to 19d (4R,5S)-methyl3-(4-cyano-3-(trifluoromethyl)phenyl)-5-methyl-2-oxooxazolidine-4-carboxylate

To a solution of (2R,3S)-Methyl2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxy butanoate (19c)(1.8 g, 5.96 mmol) in dry CH₂Cl₂ (30 mL), cooled to −78° C., DIPEA (2.93mL, 17.8 mmol) followed by Triphosgene (2.63 g, 8.9 mmol) taken in dryCH₂Cl₂ (10 mL) was added. The resulting reaction mixture was slowlywarmed to room temperature and stirred for further 16 h. Aftercompletion of reaction (by TLC), the reaction mixture was poured intoice-cold water (100 mL) and extracted with CH₂Cl₂ (2×150 mL). Thecombined organic extracts were dried over Na₂SO₄ and concentrated underreduced pressure to give the crude compound. The crude material waspurified by column chromatography to afford the oxazolidinone 19d (1.4g, 71%) as a thick liquid.

TLC: 60% EtOAc/Hexane (R_(f): 0.6).

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.27 (d, J=2.0 Hz, 1H), 8.20 (d,J=8.5 Hz, 1H), 7.85 (dd, J=8.5, 1.5 Hz, 1H), 5.37-5.35 (m, 1H),4.99-4.95 (m, 1H), 3.73 (s, 3H), 1.52 (d, J=6.5 Hz, 3H).

19d to 19e4-((4S,5S)-4-(hydroxymethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile

To a solution of (4R,5S)-methyl3-(4-cyano-3-(trifluoromethyl)phenyl)-5-methyl-2-oxooxazolidine-4-carboxylate(19d) (1.4 g, 4.26 mmol) in EtOH (80 mL), cooled to 0° C., NaBH₄ (0.192g, 5.07 mmol) was added. The resulting reaction mixture was slowlywarmed to room temperature and stirred for further 1 h. After completionof reaction (by TLC), the volatiles were removed under reduced pressureand the residue was diluted with saturated NH₄Cl solution (120 mL),stirred for 30 min at room temperature and extracted with EtOAc (2×100mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to give the crude compound which waspurified by column chromatography to furnish the alcohol 19e (1.0 gm,83%) as a white solid.

TLC: 50% EtOAc/Hexane (R_(f): 0.2)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.33 (d, J=1.5 Hz, 1H), 8.18 (d,J=8.5 Hz, 1H), 7.97 (dd, J=9.0, 2.0 Hz, 1H), 5.12 (t, J=5.5 Hz, 1H),4.70-4.65 (m, 1H), 4.48-4.46 (m, 1H), 3.66-3.62 (m, 1H), 3.53-3.49 (m,1H), 1.42 (d, J=6.0 Hz, 3H).

19e to Examples 19 and 204-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile194-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile20

19e to 19f

To a solution of4-((4S,5S)-4-(hydroxymethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile(19e) (0.5 g, 1.66 mmol) in CH₃CN (20 mL), cooled to 0° C., Dess-Martinperiodinane (1.41 g, 3.32 mmol) was added and the reaction was continuedat 0° C. for 3 h. After completion of reaction (by TLC), saturatedNaHCO₃ solution (50 mL) was added to the reaction mixture and extractedwith CH₂Cl₂ (2×50 mL). The combined organic extracts were washed withsaturated NaHCO₃ solution (50 mL). The organic layer was separated,dried over Na₂SO₄ and concentrated under reduced pressure to provide thealdehyde 19f (0.7 g) which was taken forward without purification.

TLC: 10% MeOH/DCM (R_(f): 0.6)

19f to 19g

The crude aldehyde 19f (0.7 g, 2.35 mmol) was dissolved in THF (20 mL)and cooled to 0° C. To the reaction, CsF (0.356 g, 2.34 mmol) followedby CF₃TMS (3.3 g, 23.2 mmol) was added maintaining the temperature at 0°C. The reaction was stirred at 0° C. for 3 h and quenched with saturatedNH₄Cl solution (50 mL). The reaction mixture was extracted with EtOAc(2×20 mL) and the combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to give the crude compound. Thecrude residue was passed through a short silica pad to afford the silylether 19g as a mixture of diastereomers (0.360 g, 24%) which wasimmediately used for the next step without any purification.

TLC: 30% EtOAc/Hexane (R_(f): 0.6 & 0.8)

19g to Examples 19 and 20

To crude mixture of silyl ether 19g (0.36 g, 0.81 mmol), dissolved inTHF (10 mL), KOH (0.131 g, 2.45 mmol) taken in water (5 mL) was added at0° C. The resulting reaction mixture was stirred at 0° C. for 30 min.After completion of the reaction (by TLC), the reaction mixture wasdiluted with water (30 mL) and extracted with EtOAc (2×25 mL). Thecombined organic extracts were dried over Na₂SO₄ and concentrated underreduced pressure to give the crude mixture. The crude material waspurified by column chromatography to afford 19 (0.030 g) as a whitesolid and 20 (0.040 g) as an off-white solid.

TLC: 50% EtOAc/Hexane (R_(f): 0.2 19 & 0.5 20)

Example 19

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.23 (s, 1H), 8.19 (d, J=9.0 Hz,1H), 8.09 (d, J=9.0 Hz, 1H), 6.98 (d, J=7.5 Hz, 1H), 4.93 (d, J=2.0 Hz,1H), 4.70 (d, J=5.0 Hz, 1H), 4.46 (dd, J=12.0, 7.0 Hz, 1H), 1.44 (d,J=6.5 Hz, 3H).

HPLC purity: 99.68%

Mass (ESI): 481.1[M⁺+TFA]

Example 20

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.27-8.24 (m, 2H), 7.97 (dd, J=8.5,2.0 Hz, 1H), 7.08 (d, J=6.5 Hz, 1H), 4.92-4.89 (m, 2H), 4.29-4.23 (m,1H), 1.44 (d, J=6.5 Hz, 3H).

HPLC purity: 98.78%

Mass (ESI): 481.1[M⁺+TFA]

Examples 21 and 22

21a to 21b

(2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoic acid

To a solution of D-Threonine (1.7 g, 14.2 mmol) in DMSO (10 mL), K₂CO₃(1.77 g, 12.8 mmol) followed by 2-chloro-4-fluorobenzonitrile (21a) (1.0g, 6.43 mmol) was added at room temperature. The resulting reactionmixture was heated up to 90° C. and stirred for 16 h. After completionof reaction (by TLC), the reaction mixture was brought to roomtemperature, diluted with water (10 mL) and extracted with EtOAc (2×20mL). The combined aqueous layer was acidified by citric acid (pH 3) andextracted with EtOAc (3×20 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated under reduced pressure to afford the acid21b (0.8 g, crude) as a syrup. The crude material was taken for the nextstep without purification.

TLC: 30% EtOAc/Hexane (R_(f): 0.3).

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.52 (d, J=8.5 Hz, 1H), 6.92 (s,1H), 6.88 (d, J=9.0 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 4.21-4.17 (m, 1H),4.07-4.05 (m, 1H), 3.35 (br s, 1H), 1.14 (d, J=6.5 Hz, 3H).

Mass (ESI): 253 [M⁺−1]

21b to 21c (2R,3S)-Methyl2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoate

To a stirred solution of(2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoic acid (21b)(0.8 g, 3.15 mmol) in THF (20 mL), diazomethane [prepared byN-Nitrosomethyl urea (0.8 g) and 40% KOH solution (30 mL) in ether (20mL)] was added at 0° C. under nitrogen atmosphere and stirred for 30 minat 0° C. After completion of reaction (by TLC), the volatiles wereevaporated under reduced pressure and the residue was diluted with water(20 mL) and extracted with EtOAc (2×20 mL). The combined organicextracts were dried over Na₂SO₄, and concentrated under reduced pressureto give crude residue which was purified by column chromatography tofurnish the methyl ester 21c (0.8 g, 94%) as an off white solid.

TLC: 70% EtOAc/Hexane (R_(f): 0.6)

¹H NMR (500 MHz, CDCl₃, δ in ppm): 7.42 (d, J=9.0 Hz, 1H), 6.69 (d,J=2.0 Hz, 1H), 6.54 (dd, J=9.0 Hz, 2.0 Hz, 1H), 5.10 (d, J=8.5, 1H),4.34 (br s, 1H), 3.99 (dd, J=9.0 Hz, 2.5 Hz, 1H), 3.79 (s, 3H), 2.19 (d,J=4.5 Hz, 1H), 1.31 (d, J=6.5 Hz, 3H).

Mass (ESI): 269.2 [M⁺+1]

21c to 21d (4R,5S)-Methyl3-(3-chloro-4-cyanophenyl)-5-methyl-2-oxooxazolidine-4-carboxylate

To a stirred solution of(2R,3S)-Methyl-2-(3-chloro-4-cyanophenylamino)-3-hydroxy butanoate (21c)(0.8 g, 2.98 mmol) in dry CH₂Cl₂ (30 mL), cooled to −78° C., DIPEA (1.5mL, 9.0 mmol) followed Triphosgene (1.3 g, 4.4 mmol) in CH₂Cl₂ (10 mL)was added. The resulting reaction mixture was then slowly warmed to roomtemperature and stirred for 16 h. After completion of reaction (by TLC),the reaction mixture was diluted with water (30 mL) and extracted withCH₂Cl₂ (3×20 mL). The combined organic extracts were dried over Na₂SO₄and concentrated under reduced pressure to give the crude compound. Thecrude material was purified by column chromatography to afford theoxazolidinone 21d (0.8 g, 95%) as a white solid.

TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.8)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.99 (d, J=8.0 Hz, 1H), 7.96 (d,J=2.0 Hz, 1H), 7.61 (dd, J=8.5 Hz, 2.0 Hz, 1H), 5.26 (d, J=3.5 Hz, 1H),4.93 (dd, J=6.0 Hz, 3.5 Hz, 1H), 3.73 (s, 3H), 1.50 (d, J=5.5 Hz, 3H).

21d to 21e2-Chloro-4-((4S,5S)-4-(hydroxymethyl)-5-methyl-2-oxooxazolidin-3-yl)benzonitrile

To a solution of the oxazolidinone 21d (0.8 g, 2.8 mmol) in EtOH (50mL), cooled to 0° C., NaBH₄ (0.120 g, 3.1 mmol) was added. The resultingreaction mixture was stirred at 0° C. for 2 h. After completion ofreaction (by TLC), the volatiles were evaporated under reduced pressureand the residue was diluted with cold water (30 mL) and extracted withEtOAc (3×15 mL). The combined organic extracts were dried over Na₂SO₄and concentrated under reduced pressure to give the crude compound. Thecrude material was purified by column chromatography to provide thealcohol 21e (0.7 g, 97%) as a syrup.

TLC: 50% EtOAc/Hexane (R_(f): 0.3)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.02 (d, J=2.0 Hz, 1H), 7.97 (d,J=9.0 Hz, 1H), 7.74 (dd, J=8.5 Hz, 2.5 Hz, 1H), 5.11 (t, J=5.0 Hz, 1H),4.68-4.64 (m, 1H), 4.39-4.37 (m, 1H), 3.64-3.60 (m, 1H), 3.51-3.48 (m,1H), 1.41 (d, J=6.5 Hz, 3H).

Mass (ESI): 266.1 [M⁺]

21e to Examples 21 and 222-Chloro-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile212-Chloro-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile22

21e to 21f

The alcohol 21e (0.7 g, 2.77 mmol) was dissolved in CH₃CN (50 mL) andDess-Martin periodinane (2.3 g, 5.42 mmol) was added portion wise at 0°C. The resulting reaction mixture was slowly warmed to 15° C. andstirred for 2 h. After completion of reaction (by TLC), the reactionmixture was diluted with saturated NaHCO₃ solution (30 mL) and extractedwith CH₂Cl₂ (3×30 mL). The combined organic extracts were again washedwith NaHCO₃ solution (30 mL) followed by water (30 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford the aldehyde 21f (0.5 g, crude) as a syrupwhich was used for the next step without purification.

TLC: 10% MeOH/DCM (R_(f): 0.8)

21f to 21g

The aldehyde 21f (0.5 g, 2.0 mmol) was dissolved in dry THF (50 mL) andCsF (0.3 g, 2.0 mmol) followed by CF₃-TMS (3.0 mL, 20.3 mmol) was addedat 0° C. under nitrogen atmosphere. The resulting reaction mixture wasstirred for 2 h at 0° C. and quenched with aqueous NH₄Cl solution (50mL). The reaction mixture extracted with EtOAc (3×30 mL) and thecombined organic extracts were dried over Na₂SO₄ and concentrated underreduced pressure to afford the silyl ether 21g as a mixture ofdiastereomers (0.7 g, crude) which was taken forward for the next stepwithout further purification.

TLC: 50% EtOAc/Hexane (R_(f): 0.8&0.9)

21g to Examples 21 and 22

To a solution of the crude silyl ether 21g (0.7 g, 1.8 mmol) in THF (50mL), KOH (0.3 gm, 5.4 mmol) dissolved in water (50 mL) was added at 0°C. The resulting reaction mixture was stirred at 0° C. for 1 h. Aftercompletion of reaction (by TLC), the reaction mixture was diluted withwater (30 mL) and extracted with EtOAc (3×20 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated under reduced pressureto give the crude mixture. The crude material was purified by columnchromatography to afford 21 (0.100 g) and 22 (0.100 g) both as whitesolids.

TLC: 50% EtOAc/Hexane (R_(f): 0.3 21 & 0.7 22)

Example 21

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.0-7.98 (m, 2H), 7.78 (d, J=8.5Hz, 1H), 6.97 (d, J=6.5 Hz, 1H), 4.82 (s, 1H), 4.75 (d, J=6.0 Hz, 1H),4.42 (dd, J=11.5 Hz, 7.5 Hz, 1H), 1.42 (d, J=6.5 Hz, 3H).

HPLC purity: 99.43%

Mass (ESI): 333.1 [M⁺−1]

Example 22

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.05 (d, J=8.5 Hz, 1H), 8.01 (s,1H), 7.69 (d, J=9.0 Hz, 1H), 7.10 (d, J=6.0 Hz, 1H), 4.86 (d, J=6.0 Hz,1H), 4.84 (s, 1H), 4.23-4.18 (m, 1H), 1.43 (d, J=6.0 Hz, 3H).

HPLC purity: 99.87%

Mass (ESI): 333.1 [M⁺−1]

Examples 23 and 24

(2R,3S)-2-((4-cyano-2-methyl-3-(trifluoromethyl)phenyl)amino)-3-hydroxybutanoicacid 23a to 23b

To a solution of D-Threonine (3.8 g, 31.9 mmol) in DMSO (30 mL) K₂CO₃(4.0 g, 28.9 mmol) followed by 4-fluoro-3-methyl-2-(trifluoromethyl)benzo nitrile (23a) (3.0 g, 14.7 mmol) was added at 0° C. undernitrogen atmosphere. The resulting reaction mixture was then heated upto 80° C. for 16 h. After completion of reaction (by TLC), the reactionmixture was diluted with water (30 mL) and acidified to pH-3 usingcitric acid. The aqueous layer was extracted with EtOAc (3×75 mL). Thecombined organic extracts were washed with water (3×50 mL). The organiclayer was separated dried over Na₂SO₄ and concentrated under reducedpressure to give the crude compound. The crude material was trituratedwith 10% EtOAc/hexane to afford the acid 23b (2.5 g, 57%) as whitesolid.

TLC: 30% MeOH/CH₂Cl₂ (R_(f): 0.1)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 7.66 (d, J=9.0 Hz, 1H), 6.86 (d,J=9.0 Hz, 1H), 5.59 (d, J=9.0 Hz, 1H), 4.27-4.25 (m, 1H), 4.18 (dd,J=8.5 Hz, 3.5 Hz, 1H), 2.27 (s, 3H), 1.20 (d, J=6.5 Hz, 3H).

Mass (ESI): 303.0 [M⁺+1]

23b to 23c (2R,3S)-methyl2-((4-cyano-2-methyl-3-(trifluoromethyl)phenyl)amino)-3-hydroxybutanoate

To a solution of(2R,3S)-2-((4-cyano-2-methyl-3-(trifluoromethyl)phenyl)amino)-3-hydroxybutanoicacid (23b) (2.5 g, 8.27 mmol) dissolved in THF (10 mL), cooled to 0° C.,diazomethane [prepared from N-Nitrosomethyl urea (2.5 g, 24.7 mmol) and40% KOH solution (100 mL) in ether (20 mL)] was added under nitrogenatmosphere. The reaction mixture was stirred for another 30 min at 0° C.After completion of reaction (by TLC), the reaction mixture was dilutedwith water (30 mL) and extracted with EtOAc (3×30 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure to provide the ester 23c (2.2 g, crude) as white solid whichwas pure by TLC and ¹H NMR and therefore used for the next step withoutpurification.

TLC: 50% EtOAc/Hexane (R_(f): 0.6)

¹H NMR (500 MHz, CDCl₃, 5 in ppm): 7.53 (d, J=8.5 Hz, 1H), 6.70 (d,J=8.5 Hz, 1H), 5.20 (d, J=8.0 Hz, 1H), 4.40-4.39 (m, 1H), 4.06 (dd,J=9.0 Hz, 3.0 Hz, 1H), 3.80 (s, 3H), 2.33 (s, 3H), 2.20 (d, J=4.0 Hz,1H), 1.34 (d, J=6.5 Hz, 3H).

Mass (ESI): 316.9 [M⁺+1]

23c to 23d (4R,5S)-methyl3-(4-cyano-2-methyl-3-(trifluoromethyl)phenyl)-5-methyl-2-oxooxazolidine-4-carboxylate

To a solution of (2R,3S)-methyl2-((4-cyano-2-methyl-3-(trifluoromethyl)phenyl)amino)-3-hydroxybutanoate(23c) (2.2 g, 6.96 mmol) in dry CH₂Cl₂ (20 mL), cooled to −78° C., DIPEA(3 mL, 20.7 mmol) followed by Triphosgene (3.0 g, 10.3 mmol) dissolvedin dry CH₂Cl₂ (10 mL) was added under nitrogen atmosphere. The resultingreaction mixture was allowed to warm to room temperature and stirred forfurther 16 h. After completion of reaction (by TLC), the reactionmixture was diluted with water (30 mL) and extracted with CH₂Cl₂ (3×50mL). The combined organic extracts were washed with water (3×50 mL). Theorganic layer was separated dried over Na₂SO₄ and concentrated underreduced pressure to give the crude compound. The crude material waspurified by column chromatography to afford the oxazolidinone 4 (2.1 g,88%) as an off-white solid.

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.15 (d, J=8.5 Hz, 1H), 8.0 (d,J=8.5 Hz, 1H), 5.17 (br s, 1H), 4.95 (m, 1H), 3.60 (s, 3H), 2.40 (s,1H), 1.6 (d, J=6.5 Hz, 3H).

TLC: 40% EtOAc/hexane (eluted twice) (R_(f): 0.55)

Mass (ESI): 343.6 [M⁺+1]

23d to 23e4-((4S,5S)-4-(hydroxymethyl)-5-methyl-2-oxooxazolidin-3-yl)-3-methyl-2-(trifluoromethyl)benzonitrile

To a solution of the oxazolidinone 23d (2.1 g, 6.14 mmol) in EtOH (20mL), cooled to 0° C., NaBH₄ (0.279 g, 7.3 mmol) was added under nitrogenatmosphere. The resulting reaction mixture was warmed to roomtemperature and stirred for 4 h. After completion of reaction (by TLC),the volatiles were evaporated under reduced pressure and the residue wasdiluted with saturated NH₄Cl solution (30 mL), stirred for 30 min atroom temperature and extracted with EtOAc (3×30 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure to give the crude compound. The crude material was purified bycolumn chromatography to provide the alcohol 23e (1.6 g, 84%) as anoff-white solid.

TLC: 50% EtOAc/Hexane (R_(f): 0.2)

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.07 (d, J=8.0 Hz, 1H), 7.92 (br s,1H), 5.08 (br s, 1H), 4.72-4.67 (m, 1H), 4.18 (br s, 1H), 3.46-3.42 (m,1H), 3.34-3.31 (m, 1H), 2.38 (s, 3H), 1.50 (d, J=6.0 Hz, 3H).

Mass (ESI): 315.0 [M+1]

23e to Examples 23 and 243-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile

23e to 23f

The alcohol 23e (1.6 g, 5.1 mmol) was dissolved in CH₃CN (30 mL), cooledto 0° C., and Dess-Martin periodinane (4.8 g, 11.3 mmol) was added undernitrogen atmosphere. The resulting reaction mixture was stirred at 0° C.for 4 h. After completion of reaction (by TLC), saturated NaHCO₃solution (50 mL) was added to the reaction mixture and extracted withCH₂Cl₂ (2×30 mL). The combined organic extracts were again washed withsaturated NaHCO₃ solution (2×30 mL). The organic layer was separated,dried over Na₂SO₄ and concentrated under reduced pressure to afford thealdehyde 23f (1.2 g, crude) as a white solid. The crude material wastaken to the next step without purification.

TLC: 10% MeOH/CH₂Cl₂ (R_(f): 0.4)

23f to 23g

To the solution of the aldehyde 23f (1.2 g, 3.8 mmol) in THF (20 mL),cooled to 0° C., CsF (0.574 g, 3.8 mmol) followed by CF₃TMS (4.0 mL, 38mmol) was added under nitrogen atmosphere. The reaction mixture wasstirred at 0° C. for 3 h. After completion of reaction (by TLC), thereaction mixture was quenched with saturated NH₄Cl solution (50 mL) andextracted with EtOAc (2×50 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated under reduced pressure to furnish the silylether 23g as mixture of diastereomers (1.0 g, crude). The crude materialwas carried forward for the next step without purification.

TLC: 50% EtOAc/Hexane (R_(f): 0.8)

23g to example 23 and 24

The crude silyl ether 23g (1.0 g, 2.2 mmol) was taken in THF (20 mL),cooled to 0° C., and KOH (363 mg, 6.6 mmol) taken in water (20 mL) wasadded. The resulting reaction mixture was stirred at 0° C. for 30 min.After completion of reaction (by TLC), the reaction mixture was dilutedwith water (30 mL) and extracted with EtOAc (3×30 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure to give the crude mixture. The crude residue was purified bycolumn chromatography to afford example 23 (0.093 g) as white solid andexample 24 (0.092 g) as a light yellow solid.

TLC: 50% EtOAc/Hexane [R_(f): Example 230.3 & Example 240.45]

Example 23

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.09 (br s, 1H), 8.05 (d, J=8.5 Hz,1H), 6.98 (d, J=7.0 Hz, 1H), 4.68 (t, J=5.5 Hz, 1H), 4.49 (m, 1H), 4.41(m, 1H), 2.42 (s, 3H), 1.55 (d, J=6.0 Hz, 3H).

HPLC purity: 94.44%

Mass (ESI): 381.2 [M⁺−1]

Example 24

¹H NMR (500 MHz, DMSO-d₆, δ in ppm): 8.12 (m, 2H), 7.12 (br s, 1H), 4.92(t, J=6.0 Hz, 1H), 4.58 (br s, 1H), 4.00 (t, J=7.0 Hz, 1H), 2.38 (s,3H), 1.51 (d, J=6.0 Hz, 3H).

HPLC purity: 97.84%

Mass (ESI): 383.0 [M⁺+1]

Examples 25 and 264-((R)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3-methyl-2-oxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrileExample 254-((R)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3-methyl-2-oxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrileExample 26

(R)-1-tert-butyl 5-benzyl 2-oxoimidazolidine-1,5-dicarboxylate (25a)

To a solution of Boc-D-Aspartic acid-1-benzyl ester (0.250 g, 0.77 mmol)taken in THF (4 mL), cooled to −10° C., Ethyl chloroformate (0.11 ml,1.1 mmol) and TEA (0.34 ml, (2.47 mmol) was added and stirred for 30min. NaN₃ (0.25 g, 0.386 mmol) was dissolved in water (4 ml) and addedportion wise to the reaction mixture maintaining the temperature at −10°C. The reaction mixture was slowly warmed to room temperature andstirred for further 2 h. After completion of reaction (by TLC), thereaction mixture was poured into saturated NaCl solution and extractedwith EtOAc (2×10 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated under reduced pressure to half of the volume;PhMe (15 mL) was added and heated to 80° C. for 4 h. After completion(by TLC), the reaction mixture was poured into saturated NaCl solutionand extracted with EtOAc (2×15 mL). The combined organic extracts weredried over Na₂SO₄ and purified by column chromatography to afford 25a(0.11 g, 44%) as a brown sold.

TLC: 80% EtOAc/Hexane (R_(f): 0.8)

¹H NMR (DMSO-d6, 500 MHz): δ 7.47 (br s, 1H), 7.39-7.34 (m, 5H), 5.20(d, J=1.5 Hz, 2H), 4.74 (dd, J=10.5, 3.5 Hz, 1H), 3.63-3.59 (m, 1H),3.19 (dd, J=9.5, 3.0 Hz, 1H), 1.34 (s, 9H).

(R)-1-tert-butyl 5-benzyl 3-methyl-2-oxoimidazolidine-1,5-dicarboxylate(25b)

To a solution of (R)-benzyl 2-oxooxazolidine-5-carboxylate (25a) (0.1 g0.312 mmol) in THF (2 mL), cooled to 0° C., Sodium hydride (13.9 mg,0.37 mmol, 50% dispersion in mineral oil) was added and stirred for 60min. MeI (0.048 g, 0.343 mmol) was added drop-wise to the reactionmixture, slowly warmed to room temperature and stirred for further 2 h.After completion (by TLC), the reaction mixture was poured intosaturated NH₄Cl solution (10 mL) and extracted with EtOAc (2×5 mL). Thecombined organic extracts were dried over Na₂SO₄ and concentrated underreduced pressure to provide the crude residue which was purified bycolumn chromatography to afford 25b (0.070 g, 67%) as a brown syrup.

TLC: 60% EtOAc/Hexane (R_(f): 0.3)

1H NMR (DMSO-d6, 500 MHz): δ 7.39-7.35 (m, 5H), 5.20 (s, 2H), 4.71 (dd,J=10.5, 3.5 Hz, 1H), 3.64 (t, J=10.0 Hz, 1H), 3.33 (m, 1H), 2.68 (s,3H), 1.33 (s, 9H).

(R)-benzyl 1-methyl-2-oxoimidazolidine-4-carboxylate (25c)

To a solution of (R)-1-tert-butyl 5-benzyl3-methyl-2-oxoimidazolidine-1,5-dicarboxylate (25b) (0.650 g, 1.95 mmol)in DCM (20 mL), cooled to 0° C., TFA (3 mL, 2.9 mmol) was added. Thereaction mixture was slowly warmed to room temperature and stirred forfurther 1 h. After completion (by TLC), the reaction mixture wasneutralized with saturated NaHCO₃ solution and extracted with EtOAc(3×10 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to provide the crude residue whichwas purified by column chromatography to furnish 25c (0.320 g, 70%) asoff white solid.

TLC: 60% EtOAc/Hexane (R_(f): 0.4)

1H NMR (DMSO-d6, 500 MHz): δ 7.39-7.33 (m, 5H), 6.94 (s, 1H), 5.17 (s,2H), 4.27 (dd, J=9.5, 5.0 Hz, 1H), 3.58 (t, J=9.5 Hz, 1H), 3.99 (dd,J=8.5, 4.0 Hz, 1H), 3.16 (s, 3H).

(R)-benzyl-3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxylate(25d)

To a solution of 4-bromo-2-(trifluoromethyl)benzonitrile (0.1 g, 0.4mmol) dissolved in 1,4-Dioxane (5 mL), (R)-benzyl1-methyl-2-oxoimidazolidine-4-carboxylate (25c) (0.093 g, 0.4 mmol) wasadded at room temperature followed by Cs₂CO₃ (0.260 g, 0.8 mmol) andArgon gas was purged for 30 min. To the reaction mixture Pd₂(dba)₃(0.036 g, 0.04 mmol) and Xanthphos (0.034 g, 0.058 mmol) were added atroom temperature. The resulting reaction mixture was then heated to 100°C. for 5 h. After completion (by TLC), the reaction mixture was filteredthrough celite bed. The celite bed was washed with EtOAc (2×5 mL), thefiltrates were combined, dried over Na₂SO₄ and concentrated underreduced pressure to give the crude compound. The crude residue waspurified by column chromatography to provide 25d (0.075 g, 46%) as acolourless syrup.

TLC: 60% EtOAc/Hexane (R_(f): 0.4)

1H NMR (DMSO-d6, 500 MHz): δ 8.35 (d, J=2.0 Hz, 1H), 8.04 (d, J=8.5 Hz,1H), 7.75 (dd, J=9.0, 2.5 Hz, 1H), 7.34 (t, J=3.0 Hz, 3H), 7.26-7.25 (m,2H), 5.42 (dd, J=2.5, 10.0, Hz, 1H), 5.21-5.14 (m, 2H), 3.82 (t, J=9.5Hz, 1H), 3.64 (m, 1H), 3.80 (s, 3H).

(R)-3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxylicacid (25e)

To a solution of (R)-benzyl3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxylate(25d) (0.4 g, 0.99 mmol) in MeOH (10 mL), 10% Pd/C (50 mg) was added andstirred for 2 h under H₂ atmosphere. After completion (by TLC), thereaction mixture was filtered through a celite bed, the celite bed waswashed with MeOH (10 mL), the combined filtrates were concentrated underreduced pressure to provide the acid 25e (0.280 g, 90%) as a whitesolid.

TLC: 60% EtOAc/Hexane (R_(f): 0.9)

¹H NMR (DMSO-d₆, 500 MHz): δ 13.6 (br s, 1H), 8.42 (s, 1H), 8.08 (d,J=8.5 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 5.17 (dd, J=10.0, 2.5 Hz, 1H),3.81-3.77 (m, 1H), 3.59-3.57 (m, 1H), 2.80 (s, 3H).

(R)-Methyl3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2oxoimidazolidine-4-carboxylate(25f)

To a solution of(R)-3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxylicacid (25e) (0.280 g, 0.894 mmol) in THF (10 mL), cooled to 0° C.,Diazomethane [prepared from N-Nitrosomethyl urea (0.276 g, 2.68 mmol)and 40% KOH solution (15 mL) in ether (10 mL)] was added under nitrogenatmosphere. The resulting reaction mixture was warmed up to roomtemperature and stirred for 1 h. After completion (by TLC), the reactionmixture was poured into saturated NaCl solution and extracted with EtOAc(2×10 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure to provide the crude residue whichwas purified by column chromatography to afford the methyl ester 25f(0.210 g, 72%) as a colorless syrup.

TLC: 50% EtOAc/Hexane (R_(f): 0.7)

1H NMR (DMSO-d6, 500 MHz): δ 8.47 (d, J=2.0 Hz, 1H), 8.08 (d, J=8.5 Hz,1H), 7.65 (dd, J=8.5, 2.0 Hz, 1H), 5.34 (dd, J=10.0, 2.5 Hz, 1H),3.82-3.78 (m, 1H), 3.71 (s, 3H), 3.64-3.61 (m, 1H), 2.79 (s, 3H).

2-(trifluoromethyl)-4-((R)-5-(hydroxymethyl)-3-methyl-2-oxoimidazolidin-1-yl)benzonitrile(25g)

To a solution of (R)-methyl3-(4-cyano-3-(trifluoromethyl)phenyl)-1-methyl-2-oxoimidazolidine-4-carboxylate(25f) (0.330 g, 1.01 mmol) in EtOH (20 mL), cooled to 0° C., Sodiumborohydride (0.045 g, 1.21 mmol) was added portion wise maintaining thetemperature at 0° C. The reaction mixture was slowly warmed to roomtemperature and stirred for further 6 h. After completion (by TLC) thevolatiles were removed under reduced pressure and the crude residue wasextracted with EtOAc (3×20 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated under reduced pressure to provide the crudereaction mixture which was purified by column chromatography to affordthe alcohol 25g (0.21 g, 69%) as a white solid.

TLC: 60% EtOAc/Hexane (R_(f): 0.4)

1H NMR (DMSO-d6, 500 MHz): δ 8.49 (d, J=1.5 Hz, 1H), 8.05 (d, J=8.5 Hz,1H), 7.83 (dd, J=9.0, 2.0 Hz, 1H), 5.04 (t, J=5.5 Hz, 1H), 4.5 (m, 1H),3.60-3.46 (m, 3H), 3.36 (dd, J=9.0, 3.0 Hz, 1H), 2.79 (s, 3H).

4-((R)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3-methyl-2-oxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrileExample 254-((R)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3-methyl-2-oxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrileExample 26

To a solution of2-(trifluoromethyl)-4-((R)-5-(hydroxymethyl)-3-methyl-2-oxoimidazolidin-1-yl)benzonitrile(25g) (0.1 g, 0.33 mmol) in CH₂Cl₂ (10 mL), cooled to 0° C., Dess-Martinperiodinane (0.212 g, 0.49 mmol) was added. The reaction mixture wasslowly warmed to room temperature, stirred for 1 h and quenched withsaturated NaHCO₃ solution (10 mL) and extracted with EtOAc (2×20 mL).The combined organic extracts were dried over Na₂SO₄ and concentratedunder reduced pressure to provide the aldehyde (0.99 g, crude) which wascarried forward to the next step without any purification.

TLC: 10% MeOH/DCM (R_(f): 0.5)

The crude aldehyde (0.099 g, 0.33 mmol) was dissolved in dry THF (5 mL),cooled to 0° C., CsF (0.025 g, 1.49 mmol) followed by CF₃TMS (0.213 g,0.166 mmol) were added and stirred for 1 h. After completion (by TLC),the reaction mixture was quenched with aqueous NH₄Cl and extracted withEtOAc (2×20 mL). The combined organic extracts were dried over Na₂SO₄and concentrated under vacuo to furnish the crude silyl ether (0.147 g)as a mixture of diastereomers. The crude material was used for the nextstep without purification.

TLC: 50% EtOAc/Hexane R_(f): (0.7 & 0.8)

The crude silyl ether (0.147 g, 0.334 mmol) was taken in THF (5 mL),cooled to 0° C., KOH (0.093 g, 1.67 mmol) dissolved in H₂O (2 mL) wasadded and stirred for 1 h. After completion (by TLC), the reactionmixture was diluted with H₂O (20 mL) and extracted with EtOAc (2×15 mL).The combined organic extracts were dried over Na₂SO₄ and concentratedunder vacuo to give the crude residue which was purified by columnchromatography to afford Example 25 (0.008 g) and Example 26 (0.010 g)both as white solids.

TLC: 50% EtOAc/Hexane R_(f): 0.2 (Example 25) & 0.4 (Example 26)

Example 25

1H NMR (DMSO-d6, 500 MHz): δ 8.32 (d, J=1.5, 1H), 8.07 (d, J=8.5, 1H),7.93-7.91 (m, 1H), 6.86 (d, J=7.0 Hz, 1H), 4.94 (t, J=7.5 Hz, 1H),4.34-4.30 (m, 1H), 3.64 (m, 1H), 3.47 (d, J=9.5 Hz, 1H), 2.79 (s, 3H).

Example 26

1H NMR (DMSO-d6, 500 MHz): δ 8.35 (d, J=1.5 Hz, 1H), 8.14 (d, J=9.0 Hz,1H), 7.72 (dd, J=9.0, 2.0 Hz, 1H), 6.87 (d, J=6.0 Hz, 1H), 5.02-4.99 (m,1H), 4.25-4.22 (m, 1H), 3.60 (d, J=7.0 Hz, 2H), 2.8 (s, 3H).

The following compounds were prepared from appropriate startingmaterials using similar methods as in Examples 1 to 4:

Examples 27 and 28(R)-1-(3,4-dichlorophenyl)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one(Example 27) &(R)-1-(3,4-dichlorophenyl)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one(Example 28)

Examples 29 and 302-chloro-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-oxopyrrolidin-1-yl)-3-methylbenzonitrile(Example 29) &2-chloro-4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-oxopyrrolidin-1-yl)-3-methylbenzonitrile(Example 30)

Examples 31, 32, and 332-chloro-4-((R)-2-(2,2,2-trifluoro-1-hydroxyethyl)-5-oxopyrrolidin-1-yl)benzonitrile(Example 31),2-chloro-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-oxopyrrolidin-1-yl)benzonitrile(Example 32) &2-chloro-4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-oxopyrrolidin-1-yl)benzonitrile(Example 33)

The following compounds were prepared from appropriate startingmaterials using similar methods as in Examples 7 to 24:

Examples 34 and 354-((4S,5R)-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)-3-methylbenzonitrile(Example 34) &4-((4S,5R)-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)-3-methylbenzonitrile(Example 35)

Examples 36 and 374-((4S,5R)-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile(Example 36) &4-((4S,5R)-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile(Example 37)

Examples 38 and 392-chloro-4-((4S,5R)-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)benzonitrile(Example 38) &2-chloro-4-((4S,5R)-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)benzonitrile(Example 39)

Determination of Biological Activity

In order to demonstrate the utility of the compounds of this invention,an androgen receptor binding assay was performed wherein many of thecompounds of this invention are shown to demonstrate significantaffinity for the androgen receptor. The assay was performed as specifiedby the manufacturer (Invitrogen, Madison, Wis.). Briefly, 1 μl of 10 mMcompound was added to 500 μl of AR screening buffer in a 1.5 mleppendorf tube to make a 2×10⁻⁵M stock. 10-fold serial dilutions of thetest compounds were prepared ranging in concentration from 10⁻⁵M to10⁻¹²M. Each dilution was added in triplicate to a black 384-microtiterplate. The test compounds will be diluted 2-fold in the final reaction.2×AR-Fluormone™ complex was prepared with 2 nM Flourmone AL Green™ and30 nM AR. 25 μl of 2×complex was aliquoted to each reaction well, suchthat the final reaction volume was 501 per well. Plate was sealed with afoil cover and incubated in the dark at room temperature for 4 h.Polarization values for each well were measured. The polarization valueswere plotted against the concentration of the test compound. Theconcentration of the test compound that results in half-maximum shiftequals the IC₅₀ of the test compound. As a control, a competition curvefor R1881 (methyltrienolone) was performed for each assay. Curve Fittingwas performed using GraphPad Prism® software from GraphPad™ SoftwareInc. Results are set forth in Table 1.

In Vivo Rat Model of Androgen and Anabolic Activity-Rat HerschbergerAssay

The following is a typical procedure of the in vivo evaluation of theselective androgens of this invention. In particular, this assay looksprimarily at the ability of the selective androgens of this invention toincrease muscle size in an immature, castrated rat. In addition,androgenic effects are looked at primarily by weighing the prostate andseminal vesicles. Selective compounds will show a greater increase inthe levator ani relative to the prostate and seminal vesicles whencompared to testosterone treated, castrated animals or to intact animalsthat have not been treated. Immature Sprague Dawley male rats wereobtained Charles River Laboratories (Stoneridge, N.Y.). All animals weremaintained in a temperature and humidity controlled room with a 12 hrlight: 12 hr dark cycle, with ad lib access to food (TD 291615, Teklad,Madison, Wis.) and water. Rats were anesthetized and orchidectomized(GDX) or sham surgery (SHAM) was performed. After a 7-day recoveryperiod, the animals were randomized according to weight and assigned totreatment groups (n=5), SHAM, OVX+vehicle, OVX+Cpd treated. Testosteronepropionate (TP 1 mg/kg in 5% DMSO/95% corn oil) was administered by oncedaily subcutaneous injections, while the compounds of the invention aredosed in vehicle (0.5% carboxymethylcellulose) was administered by oncedaily oral gavage. The rats were then dosed once daily for 4 days. Allanimals were euthanized via carbon dioxide inhalation 24 hs after thelast dose. The prostate, seminal vesicle and levator ani and bulbacavernous (LABC) tissues were removed, weighed and recorded. An increasein mean LABC indicates anabolic activity for that particular compoundwith regard to oral dosing typically at a maximum tested dose of between1 mg/kg and 30 mg/kg—see Table 1.

In Vivo Models of Bone Loss and Prevention

Compounds of this invention may also be assayed in vivo to determinetheir effect on preventing bone loss in animal models of bone loss.Animal models of bone loss are well-known to those of ordinary skill inthe art. Examples of bone loss models include the rat and mouseovariectomized models. Examples of such models are replete in the art,some non-limiting methods and examples are provided in Cesnjaj, et alEuropean Journal of Clinical Chemistry and Clinical Biochemistry (1991),29(4), 211-219; Y. L. Ma et al., Japanese Journal of Bone and MineralResearch 23 (Suppl.):62-68 (2005); Ornoy, et al, Osteoporosis: AnimalModels for the Human Disease; Animal Models of Human Related calciumMetabolic Disorders (1995), 105-126.

TABLE 1 Compound AR-Binding Affinity and Oral Activity Oral activity inHerscheberger assay on Compound Binding IC₅₀ (nM) LABC weight Example 114 yes Example 2 100 nt Example 3 11 yes Example 4 120 nt Example 5 530nt Example 6 No binding nt Example 7 50 yes Example 8 >1,000 nt Example9 45 yes Example 10 >1,000 nt Example 11 25 yes Example 12 933 ntExample 13 13 yes Example 14 >1,000 nt Example 15 200 nt Example16 >1,000 nt Example 17 13 yes Example 18 700 nt Example 19 4 yesExample 20 72 yes Example 21 15 yes Example 22 210 yes Example 23 33 ntExample 24 >1,000 nt Example 25 10 no Example 26 >1,000 no no = noactivity observed at highest dose tested. yes = increased LABC weightrelative to castrated vehicle control. nt = not testedAdditional data is presented in Table 2.

TABLE 2 Oral activity in Herscheberger assay on Compound Binding IC₅₀(nM) LABC weight

Example 27   62 yes Example 28  >1000 nt

Example 29   25 yes Example 30   491 no

Example 31   46 yes Example 32 nt nt Example 33   65 nt

Example 34  >1000 nt Example 35 >10000 nt

Example 36  >1000 nt Example 37  >1000 nt

Example 38   150 nt Example 39   550 nt

1. A compound according to formula I:

wherein R_(x) is CN, Cl, Br, NO₂ or R_(x1); R_(y) is CH₃, CF₃, orhalogen; R_(z) is hydrogen or optionally C₁₋₃ alkyl, C₂₋₃ alkenyl, C₁₋₃hydroxyalkyl, C₁₋₃ haloalkyl, NO₂, NH₂, OMe, halogen or OH; or R_(y) andR_(z) together form

wherein R_(y′) is optionally a substituent selected from the groupconsisting of halogen, C₁₋₃ alkyl, C₁₋₃ haloalkyl and OH; R_(x1) is a 5member heteroaryl, said heteroaryl selected from

R′ is hydrogen or optionally C₁-C₂ alkyl, CF₃, or halogen; or R_(x) andR_(y) together with the phenyl group to which they are attached form a 5member aromatic ring selected from:

wherein each R″ is independently hydrogen or optionally CF₃, or C₁-C₂alkyl; P₁ is hydrogen or a metabolically labile group; R_(a) and R_(b)are each independently selected from hydrogen or C₁-C₃ alkyl; and X isCH₂, O or NR_(c); wherein R_(c) is hydrogen or C₁-C₃ alkyl; orpharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1, wherein: R_(x) is CN; or pharmaceutically acceptable saltsthereof.
 3. A compound according to claim 1, wherein: R_(y) is CF₃ orCl; or pharmaceutically acceptable salts thereof.
 4. A compoundaccording to claim 1, wherein: R_(z) is H, CH₃, CF₃ or Cl; orpharmaceutically acceptable salts thereof.
 5. A compound according toclaim 1, wherein: R_(x) is CN; R_(y) is CF₃ or Cl; R_(z) is H or CH₃; orpharmaceutically acceptable salts thereof.
 6. A compound according toclaim 1, wherein: P₁ is hydrogen or (C═O)—C₁₋₆alkyl; or pharmaceuticallyacceptable salts thereof.
 7. A compound according to claim 1, wherein:P₁ is hydrogen.
 8. A compound according to claim 1, wherein: R_(a) andR_(b) are each independently selected from hydrogen and CH₃; orpharmaceutically acceptable salts thereof.
 9. A compound according toclaim 1, wherein: R_(a) is CH₃ and R_(b) is hydrogen; or R_(a) and R_(b)are each hydrogen; or pharmaceutically acceptable salts thereof.
 10. Acompound according to claim 1 wherein: R_(a) is CH₃ and R_(b) ishydrogen; or a pharmaceutically acceptable salt thereof.
 11. A compoundaccording to claim 1 wherein: R_(a) and R_(b) are each hydrogen; or apharmaceutically acceptable salt thereof.
 12. A compound according toclaim 1, wherein: X is CH₂, O or NCH₃; or pharmaceutically acceptablesalts thereof.
 13. A compound according to claim 1, wherein: X₁ is O; orpharmaceutically acceptable salts thereof.
 14. A compound according toclaim 1, wherein: X₁ is CH₂; or pharmaceutically acceptable saltsthereof.
 15. A compound according to claim 1 wherein the exocyclicstereochemical center is as shown in structure Ia below:

or a pharmaceutically acceptable salt thereof.
 16. A compound accordingto claim 1 wherein the exocyclic steroechemical center is as shown instructure Ib below

or a pharmaceutically acceptable salt thereof.
 17. A compound selectedfrom the following:4-((R)-2-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;3-methyl-4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;3-methyl-4-((S)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;(S)-1-(Benzo[d][1,2,3]thiadiazol-6-yl)-5-((R)-2,2,2-trifluoro1-hydroxyethyl)pyrrolidin-2-one;(S)-1-(Benzo[d][1,2,3]thiadiazol-6-yl)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one;4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;2-chloro-4-((S)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;2-chloro-4-((S)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;2-chloro-3-methyl-4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;2-chloro-3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;3-methyl-4-((R)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;3-Methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoro methyl)benzonitrile;2-chloro-3-methyl-4-((4S,5R)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;2-chloro-3-methyl-4-((4S,5R)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;2-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;2-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;2-Chloro-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;2-chloro-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;4-((R)-3-methyl-2-oxo-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)imidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile;and4-((R)-3-methyl-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)imidazolidin-1-yl)-2-(trifluoromethyl)benzonitrileor a pharmaceutically acceptable salt of any of the foregoing.
 18. Acompound selected from the following:4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;3-methyl-4-((R)-2-oxo-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile;4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;2-chloro-4-((S)-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;2-chloro-3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;3-methyl-4-((R)-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;2-chloro-3-methyl-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;2-Chloro-4-((4S,5S)-5-methyl-2-oxo-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrile;and2-Chloro-4-((4S,5S)-5-methyl-2-oxo-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)oxazolidin-3-yl)benzonitrileor a pharmaceutically acceptable salt of any of the foregoing.
 19. Apharmaceutical composition comprising a compound according to claim 1,and at least one pharmaceutically acceptable excipient.
 20. A method ofmodulating an androgen receptor in a cell, comprising the administrationof a compound according to claim 1 or a pharmaceutically acceptable saltthereof.
 21. A method of identifying a compound capable of modulating anandrogen receptor comprising contacting a cell expressing an androgenreceptor with a compound according to claim 1, and monitoring the effectof the compound on the cell.
 22. A method of treating sarcopenia,frailty, multiple sclerosis, osteoporosis, anemia, cognitive impairment,cachexia, muscular dystrophy, weak appetite, low body weight, anorexianervosa, acne, seborrhea, polycystic ovarian syndrome, hair loss, AIDswasting, chronic fatigue syndrome, short stature, low testosteronelevels, diminished libido, benign prostate hypertrophy, infertility,erectile dysfunction, vaginal dryness, premenstrual syndrome,postmenopausal symptoms, female hormone replacement therapy, malehormone replacement therapy, depression, Type II diabetes, mooddisorders, sleep disorders, memory disorders, neurodegenerativedisorders, Alzheimer's dementia, attention deficit disorder, seniledementia, coronary artery disease, hirsutism, pain, myalgia, myocardialinfarction, stroke, clotting disorders, thromboembolisms, congestiveheart disorder, low insulin sensitivity, low glucose utilization, highblood sugar, organ transplant, metabolic syndrome, diabetes, glucoseintolerance, hyperinsulinemia, insulin resistance, tooth injury, toothdisease, periodontal disease, liver disease, thrombocytopenia, fattyliver conditions, endometriosis, hot flushes, hot flashes, vasomotordisturbance, stress disorders, dwarfism, dyslipidemia, cardiovasculardisease, coronary artery disease, renal disease, thin skin disorders,lethargy, osteopenia, dialysis, irritable bowel syndrome, Crohn'sdisease, Paget's disease, osteoarthritis, connective tissue disease ordisorders, injury, burns, trauma, wounds, bone fracture,atherosclerosis, cachexia, cancer cachexia, and obesity in a mammal inneed thereof, comprising the administration to said mammal of aneffective amount of a compound, or a pharmaceutically acceptable saltthereof, according to claim
 1. 23. A method of treating prostate cancer,breast cancer, endometrial cancer, hepatocellular cancer, lymphoma,multiple endocrine neoplasia, vaginal cancer, renal cancer, thyroidcancer, testicular cancer, leukemia, and ovarian cancer in a mammal inneed thereof, comprising the administration to said mammal of aneffective amount of a compound, or a pharmaceutically acceptable saltthereof, according to claim
 1. 24-29. (canceled)
 30. A compound selectedfrom the following:(R)-1-(3,4-dichlorophenyl)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one;(R)-1-(3,4-dichlorophenyl)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-2-one;2-chloro-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-oxopyrrolidin-1-yl)-3-methylbenzonitrile;2-chloro-4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-oxopyrrolidin-1-yl)-3-methylbenzonitrile;2-chloro-4-((R)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-oxopyrrolidin-1-yl)benzonitrile;2-chloro-4-((R)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-oxopyrrolidin-1-yl)benzonitrile;4-((4S,5R)-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)-3-methylbenzonitrile;4-((4S,5R)-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)-3-methylbenzonitrile;4-((4S,5R)-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;4-((4S,5R)-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)-2-(trifluoromethyl)benzonitrile;2-chloro-4-((4S,5R)-4-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)benzonitrile;and2-chloro-4-((4S,5R)-4-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5-methyl-2-oxooxazolidin-3-yl)benzonitrileor a pharmaceutically acceptable salt of any of the foregoing. 31-37.(canceled)